Book of Abstracts - Ruhr-Universität Bochum

ISBOMC ‘10 

5th International Symposium on Bioorganometallic Chemistry 

July 05 - 09, 2010, Ruhr-Universität Bochum, Germany 

© G Gasser 

Book of Abstracts 

RESEARCH DEPARTMENT 

INTERFACIAL SYSTEMS CHEMISTRY 

DFG-Forschergruppe 630 

B i o l o g i c a l f u n c t i o n o f 

organometallic compounds

Contents 

ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum 

Foreword 2 

Sponsors 3 

Venue and travel directions 4 

General Information 6 

Conference program 7 

Oral presentations 16 

Poster presentations 58 

List of participants 143 

1

Foreword 


We welcome you to the 5 th International Symposium on Bioorganometallic Chemistry 

at the Ruhr-Universität Bochum. It is our pleasure to host you at one of the largest 

and most dynamic universities in Germany. 

Bioorganometallic Chemistry is a rapidly growing field of research at the interface of 

various disciplines. It is firmly routed in synthetic chemistry, but its applications range 

from biomedicine to medicinal and environmental analysis, modified enzymes and 

enzyme mimetics, structural studies of biomolecules and wholly new entities such as 

metallo-DNA, RNA and its analogues. The current meeting serves to showcase the 

broad variety of Bioorganometallic Chemistry, and the overwhelming interest that we 

received further underlines the vibrancy of the field. Indeed, we received many more 

applications for oral contributions than we could possibly accommodate in the 

scientific program. This has made the task of selecting a diverse and representative 

set of speakers of high scientific quality almost a daunting one, and I thank our 

colleagues for their support with this task, and all delegates for their understanding. 

We are proud to host the biggest-ever ISBOMC conference in Bochum, with > 180 

participants from more than 25 countries and all five continents. Bochum University is 

an ideal place to host such a meeting, and we will do our best to ensure that you will 

carry pleasant memories of the science as well as the venue home. Surely, this is 

only possible with the help of many caring hands and minds behind the scene, who 

have done a great job in preparing ISBOMC’10, and are ensuring its smooth 

operation during the conference. I wish to express my sincere thanks to all those 

helpers! 

I hope you will enjoy the science and the spirit of the symposium, and continue your 

efforts to make Bioorganometallic Chemistry an ongoing success story! 

Bochum, July 2010 

Nils Metzler-Nolte 

2

Sponsors 


Ruhr-Universität Bochum 

The Ruhr-Universität Bochum is one of Germany’s leading research universities. The 

University draws its strengths from both the diversity and the proximity of scientific 

and engineering disciplines on a single, coherent campus. This highly dynamic 

setting enables students and researchers to work across traditional boundaries of 

academic subjects and faculties. Host to 32,600 students and 4,700 staff, the Ruhr- 

Universität is a vital institution in the Ruhr area, which has been selected as 

European Capital of Culture for the year 2010. 

Research Department Interfacial Systems Chemistry 

The Research Department IFSC is an interdisciplinary community that brings 

together chemical and neighbouring disciplines. Researchers collaborate in the open 

spirit of a Research Department to get a fundamental and systemic understanding of 

the structural and dynamic complexity of hierarchically structured assemblies and 

complex chemical systems. 

3


Venue and travel directions 

The 5 th International Symposium on Bioorganometallic Chemistry (ISBOMC `10) will 

take place at the convention center ("Veranstaltungszentrum") of the Ruhr-Universität 

Bochum. The lecture hall (hall 2a) and poster exhibition hall (hall 1) are located in the 

convention centre (Veranstaltungszentrum) on the 4 th floor of the Mensa Building. 

The reception and registration desk is located direct in front of room 2a. For entering 

the 4 th floor please use the elevator left or right. Bochum can conveniently be 

reached by train from Frankfurt, Düsseldorf and Dortmund airport. For booking, 

reservation and timetable information we recommend the webpage from the 

Deutsche Bahn (http://www.bahn.de/i/view/GBR/en/index.shtml). From Bochum 

central station, take the subway train U35 from the basement level bound for 

"Hustadt/Querenburg" and get off after about 5 stops and 10 min travel time at the 

station "Ruhr-Universität". During daytime, the subway will go every 5 minutes. When 

leaving the platform at "Ruhr-Universität", turn right and walk past the main university 

administration building (UV on the map), the central library (UB on the map), and the 

Audimax (big bowl-shaped lecture hall) towards the mensa. You can use your 

conference badge as a valid ticket for local transport in Bochum during the 

conference from 5.7 – 9.7.2010. Please take your conference badge with you 

using local transport. 

4

Conference Venue 


Convention Centre 4 th floor: 

Convention Centre 

RUB Mensa 

Veranstaltungszentrum 

4. Floor 

5 

U35 subway station 

Ruhr-Universität 

Bus Stop 

Transfer: 

- Folkwang 

- Zeche Zollverein 

- Conference Dinner

General information 


Bus Transfers 

The buses for the excursion to the Folkwang Museum and Zeche Zollverein will wait 

10 min walk form the convention centre (marked with the red line and red dot in the 

map above). We will offer a guided tour to the buses. Departure for the guided walk 

to the bus stop is 2:30 pm on Wednesday (Excursion), July 7 th and 6:00 pm on 

Thursday (Conference dinner), July 8 th from the reception desk in the convention 

centre. After the conference dinner several busses will departure at different times 

from conference dinner location Henrichshütte. Departure times and all other 

important actual news we will announce on the screen at the reception desk. 

Poster Session 

Please hang up your posters immediately after arrival, latest till Tuesday before the 

morning session and remove them on Thursday before the conference dinner. For 

adding your poster please contacts the guides in the poster hall and use the material 

delivered at the conferewnce venue. The number of the abstract for your poster you 

will find on the poster board reserved for you. 

Internet connection 

You will have access to the internet in the convention centre via WLAN. For getting 

connected to the WWW you need a pin number you will get at the reception desk on 

demand. This number is personalized and valid for one day. You need a new 

number every day. 

6


Conference program 

7

Monday, July 5 th 2010 

16:00 to 18:00 registration 


18:00 to 18:15 opening remarks of ISBOMC'10 

18:15 to 19:00 opening lecture 

Prof. Dr. Chris Orvig (OP-1) 

Department of Chemistry 

University of British Columbia 

Bioorganometallics in Medicinal Inorganic Chemistry 

19:00 welcome reception 

8

Tuesday, July 6 th 2010 


Session I - Medicinal bioorganometallic chemistry I 

09:00 to 09:20 Prof. Dr. Ingo Ott (OP-2) 

Institute of Pharmaceutical Chemistry 

Technische Universität Braunschweig 

Bioorganometallic Solutions for the Design of Novel Gold Anticancer 

Metallodrugs 

09:20 to 09:40 Dr. Yaw-Kai Yan (OP-3) 

Nanyang Technological University, National Institute of Education 

Natural Sciences & Science Education Department 

Rhenium(I) Tricarbonyl Complexes of Benzaldehyde and Substituted 

Salicylaldehyde Dibenzyl Semicarbazones: Synthesis and 

Cytotoxicity Studies 

09:40 to 10:00 Prof. Dr. Roman Dembinski (OP-4) 


Oakland University 

Metallo-Nucleosides: Bis(dicobalt hexacarbonyl alkynyl) Derivatives 

of 2'-Deoxyuridine. Synthesis and Evaluation of Antiproliferative 

Activity Against Human Breast Cancer Cells 

10:00 to 10:20 Prof. Dr. Matthias Tacke (OP-5) 

School of Chemistry and Chemical Biology 

University College Dublin 

Novel Metallocene Anticancer Drugs: From Lead to Hit 

10:20 to 11:00 coffee break 

Session II - Medicinal bioorganometallic chemistry II 

11:00 to 11:45 Prof. Dr. Stefan Wölfl (OP-6) 

Institute of Pharmacy and Molecular Biotechnology 

Universität Heidelberg 

Transcriptional Profile of HT-29 Cells upon Treatment with Different 

Organometallic Compounds 

11:45 to 12:05 Nicolas Barry (OP-7) 

Institute of Chemistry 

University of Neuchatel 

Arene-Ruthenium Metalla-Prisms: New Drug Vectors 

12:05 to 12:25 Dr. Christian Gaiddon (OP-8) 

UMRS692 Signalisations Moléculaires et Neurodégénérescenc 

INSERM - Université de Strasbourg 

Design and Characterisation of the Anticancer Properties of 

Ruthenium(II) Organometallic Compounds: Chemical Structure 

Optimization, Transport and Regulated Signaling Pathways 

9


12:25 to 12:45 Anusch Arezki (OP-9) 

UMR 7223 Organometallic Medicinal Chemistry Group 

Ecole Nationale Supérieure de Chimie de Paris 

Synthesis and Structure-Activity Relationship of Organometallic 

Derivatives of Curcumin as Anticancer Agents 

12:45 to 14:00 lunch break 

Session III - Medicinal bioorganometallic chemistry III 

14:00 to 14:20 Prof. Dr. Domenico Osella (OP-10) 

Department of Environmental and Life Sciences 

University of Piemonte Orientale 

Synthesis, characterization and antiproliferative activity of a series of 

Pt(IV) complexes: a QSAR approach to their cytotoxicity 

14:20 to 14:40 Prof. Dr. Nataliia I. Shtemenko (OP-11) 

Department of Biophysics and Biochemistry 

Dnipropetrovs’k National University 

Influence of the Rhenium-Platinum antitumor system on tumor 

growth and blood antioxidant state 

14:40 to 15:00 Daniel Can (OP-12) 

Faculty of Inorganic Chemistry 

University of Zurich 

The [CpM(CO)3]-Moiety (M = Mn, Tc, Re) as Phenyl Ring analog - a 

Promising Strategy Towards New Drugs and Radiopharmaceuticals 

15:00 to 15:20 Dr. Elizabeth Hillard (OP-13) 



Ferrocenyl Flavonoids: Synthesis and Antiproliferative Effects 


16:00 to 18:00 poster session 

18:00 BBQ dinner: The BBQ will take place on the roof garden of the Bistro 

in the Convention centre on floor 1. You can reach the roof garden 

with the elevator from the conference hall (1 st semi-final game soccer 

world cup 2010 �). 

10

Wednesday, July 7 th 2010 


Session IV - Medicinal bioorganometallic chemistry IV 

09:00 to 09:20 Dr. Alberta Bergamo (OP-14) 

Callerio Foundation Onlus 

Preclinical Development of Metal-Based Compounds: 

Set Up of a Plastic Mouse Model 

09:20 to 09:40 Dr. Braja G. Bag (OP-15) 

Department of Chemistry and Chemical Technolgy 

Vidyasagar University 

Arjunolic acid: The First Renewable-Nano Triterpenoid in 

Bioorganometallics 

09:40 to 10:00 Dr. Gregory S. Smith (OP-16) 


University of Cape Town 

Anticancer Activity of Multinuclear Ruthenium-Arene Complexes 

Coordinated to Dendritic Poly(propyleneimine) Scaffolds 

10:00 to 10:20 Dr. Stephan Niland (OP-17) 

Center for Molecular Medicine, Department of Vascular Matrix 

Biology, Universität Frankfurt am Main 

Biofunctionalization of a Generic Collagenous Triple Helix with the 

Integrin α2β1 Binding Site 


Session V - Medicinal bioorganometallic chemistry V 

11:00 to 11:45 award lecture 

Prof. Dr. Paul Dyson (OP-18) 

Institut des Sciences et Ingénierie Chimiques 

Ecole Polytechnique Fédérale de Lausanne (EPFL) 

Organometallic Anticancer Drugs: From Simple Structures to 

Rational Drug Design Based on a Mechanistic Approach 

11:45 to 12:05 Dr. Frederik H. Kriel (OP-19) 

AuTEK Biomed, Mintek 

Biological Activity of Gold and Silver Bis(Phosphino)Hydrazine 

Complexes 

12:05 to 12:25 Prof. Dr. Mallayan Palaniandavar (OP-20) 

Centre for Bioinorganic Chemistry 

School of Chemistry, Bharathidasan University 

DNA and Protein Binding, Cleavage and Anticancer Activity of 

Organometallic (M = Ru(II), Rh(III) and Ir(III)) Arene Complexes 

11


12:25 to 12:45 PD Dr. Christian Hartinger (OP-21) 

Institute of Inorganic Chemistry 

University of Vienna 

Organometallic Pyrone and Pyridone Complexes as Anticancer 

Agents 

12:45 to 14:00 lunch 

14:00 to 18:00 excursions to Folkwang-Museum or Zeche Zollverein 

(only by separate registration) 

18:00 free evening 

(2 nd half-final game soccer world cup 2010 �) 

12

Thursday, July 8 th 2010 


Session VI - Enzymes and bioorganometallic supramolecular systems I 

09:00 to 09:45 Prof. Dr. Holger Dobbek (OP-22) 

Institut für Biologie 

Humboldt-Universität Berlin 

Metalloenzymes in the bacterial life on carbon monoxide: 

A view from structural biology 

09:45 to 10:05 Prof. Dr. Wolfgang Weigand (OP-23) 

Institut für Anorganische und Analytische Chemie 

Friedrich-Schiller-Universität Jena 

Models for the Active Site in [FeFe] Hydrogenase with 

Silicon-containing Ligands 

10:05 to 10:25 Prof. Dr. Andres Jäschke (OP-24) 

Institute of Pharmacy and Molecular Biotechnology 

Universität Heidelberg 

DNA-Organometallic Hybrid Catalysts 


Session VII - Enzymes and bioorganometallic supramolecular systems II 

11:00 to 11:45 Prof. Dr. Yoshihito Watanabe (OP-25) 

Graduate School of Science, Department of Chemistry 

Nagoya University 

Construction of Organometalloenzymes 

11:45 to 12:05 Dr. Fabio Zobi (OP-26) 


University of Zürich 

CO Releasing Properties of cis-trans-[Re II (CO)2Br2L2]n Complexes: 

A Feature Modulated by Ligand Variation for a True Chance at 

Medicinal Applications 

12:05 to 12:25 Dr. João D. G. Correia (OP-27) 

Unidade de Ciências Químicas e Radiofarmacêuticas, ITN 

Nitric Oxide Synthase Targeting with 99m Tc(I)/Re(I) Complexes 

12:25 to 12:45 Dr. Jason M. Lynam (OP-28) 


University of York 

Mechanistic and Synthetic Studies of Bio-compatible Carbon 

Monoxide-Releasing Molecules 

12:45 to 14:00 lunch break 

13


Session VIII - Enzymes and bioorganometallic supramolecular systems III 

14:00 to 14:45 Prof. Dr. Morten Meldal (OP-29) 

Carlsberg Laboratory 

Peptide-carbenes and peptide-phosphines transition metal catalysts 

for “Green” solid phase catalysts 

14:45 to 15:05 Dr. Pratima Srivastava (OP-30) 



Construction of an Immunosensor via Copper-Free ‘Click’ Reaction 

Between Azido SAMs and Alkynyl Fischer Carbene Complex. 

Application to the detection of Staphyloccal Enterotoxin A 

15:05 to 15:25 Prof. Dr. Toshiyuki Moriuchi (OP-31) 

Department of Applied Chemistry, Graduate School of Engineering 

Osaka University 

Polypeptides Induced Self-Association and Emission Properties of 

Platinum(II) and Gold(I) Complexes 


Session IX - Enzymes and bioorganometallic supramolecular systems IV 

16:00 to 16:45 Prof. Dr. Gerard van Koten (OP-32) 

Organic Chemistry and Catalysis, Faculty of Science 

Utrecht University 

Homogeneous and Bio-Catalysis in Concert: Hybrids of ECE-pincer 

Organometallics and Lipases 

16:45 to 17:05 Jeremy Zimbron (OP-33) 


University of Basel 

Chemo-Genetic Optimization of DNA Recognition by Metallodrugs 

using a Presenter Protein Strategy 

17:05 to 17:25 Dr. Johannes A. Eble (OP-34) 

Center for Molecular Medicine, Department of Vascular Matrix 

Biology, Universität Frankfurt am Main 

RAPTA-T interacts with �1�1 integrin at the molecular level 

18:00 departure for conference dinner at Henrichshütte 

14

Friday, July 9 th 2010 

Session X - Bioimaging I 


09:00 to 09:45 Prof. Dr. John Valliant (OP-35) 


McMaster University 

TBA 

09:45 to 10:05 Anica Dose (OP-36) 

Functional Materials Group, School of Physical Science 

University of Kent 

Syntheses of New Isomeric Analogues of HYNIC for Evaluation 

as a Bifunctional Chelator for Technetium-99m 

10:05 to 10:25 Prof. Dr. Emanuela Licandro (OP-37) 

Dipartimento di Chimica Organica e Industriale 

University of Milano 

Fluorescent Conjugates Between Dinuclear Rhenium(I) Complexes 

and Peptide Nucleic Acids (PNA) for Cell imaging and DNA Targeting 


Session XI - Bioimaging II 

11:00 to 11:45 Prof. Dr. Kenneth Kam-Wing Lo (OP-38) 

Department of Biology and Chemistry 

City University of Hong Kong 

Design of Cyclometalated Iridium(III) Polypyridine Complexes as 

Luminescent Biological Labels and Probes 

11:45 to 12:05 Dr. Anne Vessières (OP-39) 



Subcellular Imaging of a Re(CO)3 Complex by Photothermal Infrared 

Spectromicroscopy (PTIR) 

12:05 to 12:25 Prof. Dr. Edward Rosenberg (OP-40) 

Department of Chemistry and Biochemistry 

University of Montana, Missoula 

Dynamical Studies of Bioconjugated Luminescent Ruthenium 

Complexes in Lipid Vesicles 

12:25 to 12:45 Dr. Gilles Gasser (OP-41) 


University of Zürich 

Multi-Organometallic-Containing Peptide Nucleic Acids: Preparation 

and Biological Applications 

12:45 to 13:00 closing remarks and announcement of ISBOMC'12 

15


Oral presentations 

16

OP-1 


Bioorganometallics in Medicinal Inorganic Chemistry 

Chris Orvig *a 

a Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British 

Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. E-mail: orvig@chem.ubc.ca 

Bioorganometallic chemistry was an oxymoron in the 1970s when Pt compounds emerged for cancer 

chemotherapy and Tc compounds took flight as nuclear medicine imaging agents. At that time, the 

speaker fastidiously avoided working with technetium carbonyl compounds when he was a graduate 

student! Now, thanks to the effort of this community, bioorganometallic chemistry plays a valuable 

role to the larger fields of medicinal inorganic chemistry and medicinal chemistry. 

Efforts in the speaker's labs to develop organometallic compounds for therapy and diagnosis will be 

outlined, focussing on recent results in antimalarial and imaging applications. 

17

OP-2 


Bioorganometallic Solutions for the Design 

of Novel Gold Anticancer Metallodrugs 

Ingo Ott, *a Riccardo Rubbiani, a Igor Kitanovic, b Hamed Alborzinia, b Suzan Can, b Stefan Wölfl, b 

Liliane A. Onambele, c Aram Prokop c 

a Technische Universität Braunschweig, Institute of Pharmaceutical Chemistry, Beethovenstr. 55, 

38106, Braunschweig, Germany, b Ruprecht-Karls-Universität Heidelberg, Institut für Pharmazie und 

Molekulare Biotechnologie, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany c) Kliniken der 

Stadt Köln GmbH; E-mail: ingo.ott@tu-bs.de 

Motivated by the success of gold species in the treatment of rheumatoid arthritis and by the promising 

outcome of several preclinical studies increasing efforts have been made to develop gold complexes 

also for the use in cancer chemotherapy. Concerning the mode of drug action thioredoxin reductase 

(TrxR), an enzyme closely related to glutathione reductase (GR), is nowadays considered as the most 

relevant molecular target based on the high selectivity of gold species for this enzyme and its 

substantial involvement in tumor growth and progression. 1-3 

Here we wish to present our most recent results obtained with gold(I) bioorganometallics featuring Nheterocyclic 

carbene (NHC) derived ligands (see the figure below for a relevant example) in 

comparison to relevant non organometallic gold(I) phosphine complexes such as auranofin. 

Promising antiproliferative effects were noted in MCF-7 breast adenocarcinoma as well as HT-29 

colon carcinoma cells and the target compounds were found to be strong and selective inhibitors of 

TrxR with an increased stability against glutathione. More detailed studies on a selected gold(I) NHC 

complex revealed a strong induction of apoptosis and reactive oxygene species (ROS) formation, 

antimitochondrial properties, as well as distinct effects on cellular metabolism. 

References 

N 

N 

18 

Au Cl 

Figure: example for a bioactive gold(I) NHC complex 

1. I. Ott, Coord. Chem. Rev. 2009, 253, 1670-1681. 

2. A. Bindoli, M. P. Rigobello, G. Scutari, C. Gabbiani, A. Casini, L. Messori, Coord. Chem. Rev. 

2009, 253, 1692-1707. 

3. P. J. Barnard, S. J. Berners-Price, Coord. Chem. Rev. 2007, 251, 1889-1902.

OP-3 


Rhenium(I) Tricarbonyl Complexes of Benzaldehyde and Substituted 

Salicylaldehyde Dibenzyl Semicarbazones: Synthesis and Cytotoxicity Studies 

Yaw-Kai Yan, *a Siti Munira bte Haidad Ali, a and Peng-Foo Peter Lee a 

a Nanyang Technological University, National Institute of Education, Natural Sciences & Science 

Education Department, 1 Nanyang Walk, Singapore 637616. E-mail: yawkai.yan@nie.edu.sg 

Semicarbazones and their metal complexes are attracting interest due to their potential medicinal 

applications. 1 In particular, metal complexes of salicylaldehyde semicarbazones were shown to have in 

vitro anti-cancer activity. 2 Since rhenium(I) tricarbonyl complexes of bis(diphenylphosphinomethyl) 

amines and 2-(dimethylamino)ethoxide also show cytotoxic activity against several murine and human 

cancer cell lines, 3 we embarked on a study of the cancer cell cytotoxicity of rhenium(I) tricarbonyl 

complexes of N,N-disubstituted salicylaldehyde semicarbazones (SSCs), [ReBr(CO)3(SSC)]. It was 

found that these complexes exhibit moderate to high cytotoxicities towards MOLT-4 cells. 4 In this 

paper, we report our recent work on the synthesis and cytotoxicity screening of benzaldehyde and 

substituted salicylaldehyde dibenzyl semicarbazones, and their rhenium(I) tricarbonyl complexes 

(Figure). The results show that complexes 2, 3 and 5 are strongly cytotoxic against MOLT-4 cells. 

References 

1. H. Beraldo, D. Gambino, Minirev. Med. Chem. 2004, 4, 31-39. (b) Z. Afrasiabi, E. Sinn, W. Lin, Y. 

Ma, C. Campana, S.B. Padhyé, J. Inorg. Biochem. 2005, 99, 1526-1531. (c) J. Rivadeneira, D.A. 

Barrio, G. Arrambide, D. Gambino, L. Bruzzone, S.B. Etcheverry, J. Inorg. Biochem. 2009, 103, 633- 

642. 

2. (a) J. Patole, S. Padhye, M.S. Moodbidri, N. Shirsat, Eur. J. Med. Chem. 2005, 40, 1052-1055. (b) 

P. Noblia, M. Vieites, B. Parajon-Costa, E. Baran, H. Cerecetto, P. Draper, M. Gonzalez, O. Piro, E. 

Castellano, A. Azqueta, A. de Cerain, A. Monge-Vega, D. Gambino, J. Inorg. Biochem. 2005, 99, 

443-451. 

3. (a) J. Zhang, J.J. Vittal, W. Henderson, J. Wheaton, I.H. Hall, T.S.A. Hor, Y.K. Yan, J. Organomet. 

Chem. 2002, 650, 123-132. (b) W. Wang, Y.K. Yan, T.S.A. Hor, J.J. Vittal, J.R. Wheaton, I.H. Hall, 

Polyhedron 2002, 21, 1991-1999. 

4. J. Ho, W. Y. Lee, P. F. P. Lee, Y. K. Yan, J. Inorg. Biochem., submitted. 

19

OP-4 


Metallo-Nucleosides: Bis(dicobalt hexacarbonyl alkynyl) Derivatives of 

2'-Deoxyuridine. Synthesis and Evaluation of Antiproliferative Activity Against 

Human Breast Cancer Cells 

Roman Dembinski, *a Przemyslaw Wyrebek. a Agnieszka Mikus. a Adam Sniady,. a Laura Hamel, b 

and Ingo Ott *b 

a Oakland University, Department of Chemistry, 2200 N. Squirrel Rd., 48309-4477, Rochester, MI, 

USA. b Technische Universität Braunschweig, Institute of Pharmaceutical Chemistry, Beethovenstr. 

55, 38106 Braunschweig, Germany, E-mail: dembinsk@oakland.edu 

In continuation of synthetic pursuit of metallo-nucleosides, in particular dicobalt 

hexacarbonyl 5-alkynyl-2'-deoxyuridines, 1 novel compounds with two alkynyl groups were 

synthesized starting from 5-iodo-2'-deoxyuridine (selected example is illustrated below). The 

complexes have been examined for their anti-cancer activity in vitro against MCF-7 and 

MDA-MB-231 human breast cancer cell lines or HT-29 (colon carcinoma). The results were 

compared to activity of non-coordinated alkynyl precursors. 

References 

HO 

O 

HN 

O 

OH 

O 

N 

(CO) 3 

Co Co(CO) 3 

20 

H 

Co(CO) 3 

Co(CO) 3 

1. (a) C. D. Sergeant, I. Ott, A. Sniady, S. Meneni, R. Gust, A. L. Rheingold, R. Dembinski, Org. 

Biomolec. Chem. 2008, 6, 73-80. (b) I. Ott, B. Kircher, R. Dembinski, R. Gust, Expert Opin. 

Therapeutic Pat. 2008, 18, 327-336.

OP-5 


Novel Metallocene Anticancer Drugs: From Lead to Hit 

Matthias Tacke a 

a Centre for Synthesis and Chemical Biology, Conway Institute 

UCD School of Chemistry and Chemical Biology, Belfield, Dublin 4, Ireland. 

E-mail: matthias.tacke@ucd.ie 

Titanocene dichloride derivatives like Titanocene Y were extensively investigated in vitro, in vivo 

and ex vivo during the last years. 1-5 In addition, details about the mechanism of action became 

available, which allowed for choosing renal-cell cancer as one of the appropriate targets. More 

recently, the successful substitution patterns of the titanocenes were transmetallated onto vanadium 

which has led to isostructural vanadocene dichloride compounds. 6, 7 These compounds have started 

their preclinical evaluation process with respect to their cytotoxicity and anti-angiogenic activity in 

vitro and their tumor volume control and toxicity in vivo. The results allow for the first to look at the 

direct comparison of these two promising classes of metallocene compounds; this might allow to 

answer the question, which metal is the most promising for further development. 

References 

1. Bioorganometallic Fulvene-Derived Titanocene Anticancer Drugs, K. Strohfeldt, M. Tacke, Chem. 

Soc. Rev., 2008, 37, 1174-1187. 

2. In Vitro Anti-Tumor Activity of Bridged and Unbridged Benzyl-Substituted Titanocenes, G. Kelter, 

N. Sweeney, K. Strohfeldt, H.-H. Fiebig, M. Tacke, Anti-Cancer Drugs, 2005, 16, 1091-1098. 

3. Antitumor Activity of Titanocene Y in Xenografted Caki-1 Tumors in Mice, I. Fichtner, C. 

Pampillón, N. J. Sweeney, K. Strohfeldt, M. Tacke, Anti-Cancer Drugs, 2006, 17, 333-336. 

4. Antitumor Activity of Titanocene Y in Freshly Explanted Human Breast Tumors and in Xenografted 

MCF-7 Tumors in Mice, Anti-Cancer Drugs, 2007, 18, 311-315. 

5. Antiproliferative Activity of Titanocene Y against Tumor Colony Forming Units, O. Oberschmidt, 

A.-R. Hanauske, C. Pampillón, K. Strohfeldt, N. J. Sweeney, M. Tacke, Anti-Cancer Drugs, 2007, 18, 

317-321. 

6. Novel Benzyl-Substituted Vanadocene Anticancer Drugs, B. Gleeson, J. Claffey, M. Hogan, H. 

Müller-Bunz, D. Wallis, M. Tacke, J. Organometal. Chem., 2009, 694, 1369-1374. 

7. Synthesis and Cytotoxicity Studies of Fluorinated Derivatives of Vanadocene Y, B. Gleeson, J. 

Claffey, A. Deally, M. Hogan, L. M. Menéndez Méndez, H. Müller-Bunz, S. Patil, D. Wallis, M. 

Tacke, Eur. J. Inorg. Chem., 2009, 2804-2810. 

Acknowledgement: Support is acknowledged from CESAR, COST, HEA, CSCB and UCD. 

21

OP-6 

ISBOMC `10 5.7 – 9.7 Ruhr-Universität Bochum 



Igor Kitanovic, a Ana Kitanovic, a Hamed Alborzinia, a Suzan Can, a Pavlo Holenya, a Elke Lederer, a 

Hans-Günther Schmalz, b Annegret Hille, c Ronald Gust, c Ingo Ott, d Aram Prokop, e Melanie Oleszak, f 

Yvonne Geldmacher, f William S. Sheldrick, f Gilles Gasser, g Nils Metzler-Nolte h and Stefan Wölfl *a 

a Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Germany, b Institute of 

Inorganic Chemistry, University of Cologne, Germany, c Institute of Pharmacy, Department of 

Pharmaceutical Chemistry, Freie Universität Berlin, Germany, d Institute of Pharmaceutical 

Chemistry, Technische Universität Braunschweig, Germany, e Cologne City Hospital, Department of 

Oncology, Cologne, Germany, f Faculty of Chemistry and Biochemistry, Department of Analytical 

Chemistry, University Bochum, g Institute of Inorganic Chemistry, University of Zurich, h Faculty of 

Chemistry and Biochemistry, Department of Bioinorganic Chemistry, University of Bochum. email: 

igor.kitanovic@urz.uni-heidelberg.de, wolfl@uni-hd.de 

In the past several decades metal compounds containing platinum became an essential part of many 

clinical protocols for anti-cancer therapy. Considered to be relatively unspecific compounds that block 

DNA-replication and cell cycle progression, metal-containing compounds were not in the research 

focus of medicinal chemistry. New developments in the chemistry of (bio-)organometallic compounds 

however lead to the discovery of several unexpected highly specific activities of new organometallic 

compounds and opened new important perspectives in this field. 

For cancer therapy cancer cell specific toxicity and apoptosis induction are highly desirable features of 

new potential drugs. Within our collaborative network a wide range of new (bio-)orgamometallic 

compounds were developed that show very distinct cytotoxic properties suggesting that rather than 

acting through a common mechanism different cellular targets are responsible for cytotoxicity and cell 

death induction. 

We will present a comprehensive analysis of the cellular response of human colorectal 

adenocarcinoma cells HT29 with very diverse organometallic compounds: ranging from FeIIsalophenes, 

through more classical bioorganometallic compounds to bioorganometallic compounds 

derived from established (non-metal containing) drugs. To elucidate their specific activity profile, 

standard cell based assays were combined with genome wide gene expression profiling using 

affymetrix gene expression arrays. Although the substances represent a wide range of different 

structures and metal cores, they all are highly cytotoxic and clearly induce apoptosis in HT-29 cells. 

For gene expression profiling concentrations just below the IC50 (cytotoxicity) were chosen to obtain 

more compound specific alterations in gene expression rather then common cytotoxicity profiles, in 

addition mRNAs were collected at different time points critical in the cellular response upon 

treatment. 

The results obtained show similar response characteristics, but also very compound specific changes. 

This clearly indicates very distinct biological properties and suggests common response mechanisms 

as well as high selectivity and target specificity. 

List of compounds: Hi41, CoASS (AG Gust), MH1 (AG Scheldrick), MeN69 (AG Schmaltz), 

FcOHTAM3, ReGG1 (AG Metzler-Nolte) 

This work is supported by the DFG as part of the Forschergruppe FOR630. 

22

OP-7 


Arene-Ruthenium Metalla-Prisms: New Drug Vectors 

Nicolas Barry a and Bruno Therrien *a 

a University of Neuchatel, Faculty of Science, Institute of Chemistry, 51 Ave de Bellevaux, 2000, 

Neuchatel, Switzerland. E-mail: bruno.therrien@unine.ch 

Based on “enhanced permeability and retention” (EPR) effect, passive targeting of tumours appears as 

a promising solution against the general toxicity, resistance mechanisms and side effects of classical 

chemotherapeutics. 1 Thus, large drug delivery systems offer in general a better selectivity as compared 

to small molecules. Large drug delivery vectors include micelles, nanoparticles and dendrimers; 

however, we proposed some years ago a new type of water soluble capsule built from arene-ruthenium 

units. These intrinsic cytotoxic metalla-prismatic cages allowed encapsulation of palladium or 

platinum complexes inside their cavities, 2 as well as the encapsulation of aromatic molecules. 3 

Moreover, the uptake of encapsulated molecule into cancer cells via fluorescence microscopy was also 

studied. 4 

Host-guest properties have been recently observed with a slightly different arene-ruthenium metallaprism, 

which does not really change neither the uptake of the guest into cancer cells nor the 

cytotoxicity. However, fluorescence microscopy assays seem to show a faster release of the guest 

molecule inside cancer cells, thus opening new perspectives for these metalla-cages. These new results 

will be the focus of this presentation. 

References 

1. Y. Matsumura, H. Maeda, Cancer Res. 1986, 46, 6387. 

2. B. Therrien, G. Süss-Fink, P. Govindaswamy, A. K. Renfrew, P. J. Dyson, Angew. Chem. Int. Ed. 

2008, 47, 3773. 

3. J. Mattsson, P. Govindaswamy, J. Furrer, S. Sei, K. Yamaguchi, G. Süss-Fink, B. Therrien, 

Organometallics 2008, 27, 4346. 

4. O. Zava, J. Mattsson, B. Therrien, P. J. Dyson, Chem. Eur. J. 2010, 16, 1428. 

23

OP-8 


Design and Characterisation of the Anticancer Properties of Ruthenium(II) 

Organometallic Compounds: Chemical Structure Optimization, Transport 

and Regulated Signaling Pathways 

Christian Gaiddon, a* Jenny Marjorie, a Meng Xiangjun, a Leyva L. Mili, b Isabelle Gross, e 

Sébastien Harlepp, c Pascal Hébraud, c Anne Boos, d Claude Sirlin, b Michel Pfeffer, b 

and Jean-Philippe Loeffler a 

aUMRS692 INSERM - Université de Strasbourg, Signalisations Moléculaires et Neurodégénérescence, 

11 rue Humann, Strasbourg, France 

b UMR 7177 CNRS- Université de Strasbourg, Institut de Chimie, Strasbourg, France 

c UMR 7504 CNRS, IPCMS, Strasbourg, France 

d UMR 7178 IPHC-DSA, ULP, CNRS, ECPM, Strasbourg France 

e UMRS682 INSERM - Université de Strasbourg, Strasbourg, France 

gaiddon@unistra.fr 

Cisplatin-derived anticancer therapy has been used for three decades despite its side effects. Other 

types of organometallic complexes, namely some ruthenium-derived compounds (RDCs), which 

would display cytotoxicity through different modes of action, might represent alternative therapeutic 

agents. We have studied both in vitro and in vivo the biological properties of a new class of RDCs that 

contain a covalent bond between a ruthenium(II) atom and a carbon. We showed that these RDC 

inhibited the growth of various tumors implanted in mice more efficiently than cisplatin. Importantly, 

in striking contrast with cisplatin, some of these RDCs did not cause severe side effects on the liver, 

kidneys, or the neuronal sensory system. We analyzed the mode of action of these RDC and 

demonstrated that they interacted poorly with DNA and induced only limited DNA damages compared 

to cisplatin, suggesting alternative transduction pathways. Indeed, we found that target genes of the 

endoplasmic reticulum (ER) stress pathway, such as Bip, XBP1, PDI, and CHOP, were activated in 

RDC-treated cells. Induction of the transcription factor CHOP, a crucial mediator of ER stress 

apoptosis, was also confirmed in tumors treated with RDCs. Activation of factor CHOP led to the 

expression of several of its target genes, including pro-apoptotic genes. In addition, the silencing of 

CHOP by RNA interference significantly reduced the cytotoxicity of RDCs. Altogether, our results 

led us to conclude that RDCs act by an atypical pathway involving CHOP and ER stress, and thus 

might provide an interesting alternative for anticancer therapy. 

Based on these results, we have now developed new and optimized RDCs with an enhanced 

cytotoxicity. We show that they have indeed a greater toxicity in vitro, which is linked to the 

activation of different signaling pathways. In order to have a better understanding of the mode of 

action of RDCs, we have analyzed their import into cells and compared the transcriptome regulated by 

cisplatin and RDCs. We identified various signaling pathways regulated specifically by RDCs that 

allowed us to present an interesting and global hypothesis linking the anticancer effect of RDCs, their 

redox activity and the alteration of the cellular metabolism. 

24

OP-9 


Synthesis and Structure-Activity Relationship of Organometallic Derivatives 

of Curcumin as Anticancer Agents 

Anusch Arezki, Emilie Brulé,* and Gérard Jaouen 

Chimie ParisTech (ENSCP), Laboratoire Charles Friedel (UMR 7223), 

Organometallic Medicinal Chemistry Group 

11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France 

E-mail: anusch-arezki@chimie-paristech.fr 

Turmeric and especially its main and active constituent curcumin have traditionally been used as a 

food preservative, as well as a natural remedy in Ayurvedic and Chinese medicine for centuries. But it 

is only within the past few years that modern research has focused on curcumin's biological properties 

(antioxidant, anti-inflammatory...) and in particular on the extraordinary actions of curcumin in 

preventing and fighting cancer. Curcumin has at least a dozen separate ways of interfering with cancer 

progression, but at the same time preserving normal cells. 1 

In our laboratory, we chose different curcuminoids as starting materials to lead to a novel class of 

bioorganometallic anticancer agents by covalently grafting different organometallic ligands to the 

curcuminoid skeleton. The synthesis of the new ferrocenyl molecules was primarily done by 

substitution of the central carbon of the curcuminoids, 2 which has shown to have a crucial influence on 

activity against some cancer cells. 3 The new complexes were tested in vitro on different cancer cell 

lines, such as prostate and skin (melanoma), and showed promising cytotoxic effects on all types. For 

some of the ferrocenyl-curcuminoid derivatives, enhanced cytotoxic activity was observed compared 

to the organic curcuminoid analogues, with up to a 3- and 4-fold improvement on prostate and 

melanoma cells, respectively. 

MeO 

HO 

OH O 

Curcumin 

OMe 

OH 

25 

MeO 

R 1 

OH O 

R 2 R 2 

R 1 : H, OH, OMe 

R 2 : H, OMe 

= organic linker 

Curcumin and ferrocenyl derivatives of several curcuminoids 

Due to encouraging results in vitro, the National Institute of Health of the United States is currently 

screening, in collaboration with the National Cancer Institute, one selected ferrocenyl curcuminoid on 

60 different cancer cell lines (colon, lung, central nervous system,…). Primary single dose testing 

revealed a particular selectivity of the compound for certain types of cancer in vitro, which has led to 

more detailed investigations, presently ongoing. 

Acknowledgement to the Gottlieb-Daimler and Carl-Benz Foundation (Germany) and the Association 

pour la Recherche sur le Cancer (ARC) (France) for PhD funding. 

References 

1. A. Goel, A. B. Kunnumakkara, B. B. Aggarwal, Biochem. Pharmacol. 2008, 75, 787-809. 

2. A. Arezki, E. Brulé, G. Jaouen, Organometallics 2009, 28, 1606-1609. 

3. L. Lin, Q. Shi, A. K. Nyarko, K. F. Bastow et al. J. Med. Chem. 2006, 49, 3963-3972. 

4. P. Anand, A. B. Kunnumakkara, R. A. Newman, B. B. Aggarwal, Mol. Pharm. 2007, 4, 804-818. 

Fe 

OMe 

R 1

OP-10 


Synthesis, characterization and antiproliferative activity of a series of Pt(IV) 

complexes: a QSAR approach to their cytotoxicity 

Domenico Osella, a Paola Gramatica, b Ester Papa, b Mara Luini, b Elena Monti, b Marzia B. Gariboldi, b 

Mauro Ravera, a Elisabetta Gabano, a and Luca Gaviglio a 

a University of Piemonte Orientale “A. Avogadro”, Department of Environmental and Life Sciences, 

Viale Michel 11, 15121, Alessandria, Italy. b Department of Structural and Functional Biology, 

University of Insubria, Via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. E-mail: 

domenico.osella@mfn.unipmn.it 

Octahedral Pt(IV) complexes are usually supposed to behave as antitumor pro-drugs: most of them can 

be reduced by the hypoxic environment of the tumour tissue to square planar Pt(II) via a two electron 

reduction and loss of axial ligands. Both axial and equatorial ligands play an important role in setting 

the redox potential into the biological window and modulating the lipophilicity of Pt(IV) complexes, 

whereas the two carrier groups (N-based) determine the antiproliferative potency of the drug. 

A large series of Pt(IV) complexes containing different ligands was synthesized, characterized 

and tested for in vitro antitumor activity against ovarian carcinoma, A2780, and colon 

adenocarcinoma, HCT116, cell lines. 

A quantitative structure-activity relationship (QSAR) analysis was performed on this series of Pt(IV) 

complexes to find a relationship among cytotoxicity (IC50), reduction peak potential (Ep), partition 

coefficient (log Po/w) and theoretical molecular descriptors. The whole set of descriptors was used as 

an input set for modeling, in order to identify different structural features of Pt(IV) complexes related 

to the in vitro cytotoxicity. 

In the resulting models, a lipophilic descriptor (i.e log Po/w or number of secondary sp 3 carbon atoms, 

nCs) plus an electronic descriptor (Ep, number of oxygen atoms, nO, or total polar surface area, 

TPSA(NO)) is necessary for the optimal modeling. This results support the general findings that the 

biological behavior of Pt(IV) complexes is related to their uptake, reduction, and structure of the 

corresponding Pt(II) metabolites. 

26

OP-11 


Influence of the Rhenium-Platinum antitumor system on tumor growth and blood 

antioxidant state 

Nataliia I. Shtemenko, a Alexander V. Shtemenko b 

a Department of Biophysics and Biochemistry, Dnipropetrovs’k National University, 72 Gagarin 

avenue, Dnipropetrovs’k 49010, Ukraine, b Department of Inorganic Chemistry, Ukrainian State 

Chemical Technological University, Gagarin avenue 8, Dnipropetrovs’k 49005, Ukraine. E-mail: 

ashtemenko@yahoo.com 

The novel antitumor system including cluster rhenium compounds and cisplatin (Re-Pt 4:1 system) 

has been recently presented 1 that was effective in the model of rat’s specific Guerink carcinoma T8 

and in the majority of experiments led to disappearance of cancer cells. The approach to circumvent 

such drawbacks of the drugs on the base of heavy metal compounds as dose-limiting toxicities 

(nephro-, hepato-, neurotoxicity, etc.) by encapsulation of the drug into a nanoparticle prevents byside 

interactions is a very promising strategy in medicine 2 . Oxidative stress-induced activation of 

NADPH oxidase and peroxisome proliferators-activated receptors, alterations of redox state of 

binding proteins, DNA mutations and induction of early response genes and hematopoietic activation, 

etc. seem to be common elements in the induction of hyperplasia, neoplasia, cancer metastasis, and 

angiogenesis. In the present work we show application of different nano-preparations of 20 – 100 nm 

size, nanoliposomes and solid nanoparticles loaded with Re-Pt system or with its components in 

different ratios in the model of tumor growth. The cluster rhenium compounds dichlorotetra-�isobutiratodirhenium(III) 

[Re2(i-C3H7CO2)4Cl2] (Re1) and cis-Re2(C10H15COO)2Cl4·2(CH3)2SO (Re2) 

tetrachlorodi-µ-adamantylcarboxylatodirhenium(III) with dimethyl sulfoxide as axial ligands were 

the matter of concern. Parameters of oxidative stress in blood of experimental animals were 

measured. Intensity of peroxide oxidation process (POL), activity of catalase (C) and superoxide 

dismutase (SOD) in plasma and red blood cells were very sensitive to tumor growth and to its 

prevention by the system. Introduction of the Re-Pt system in nanoliposomes and nanoparticles did 

not influence on the inhibition of tumor growth, except experiments, where quantity of cisplatin in 

capsules were lower (1:8). The lowering of the size of the introduced liposomes and particles did not 

influence on the intensity of POL: concentration of malonic dialdehyde was not changed. Activities 

of SOD and C in plasma and erythrocytes were higher, especially in experiments with solid 

nanoparticles (in 1.8 times in comparison with application of ordinary liposomes). This activation of 

the antioxidant enzymes was independent from the size of the tumor and remained on the high level 

even in those experiments, where ratio of introduced Rhenium compound : cisplatin was 1 : 8. In this 

work we show also that influence of rhenium compounds on the enzymes activity is dependent from 

the structure of organic radical in the investigated rhenium substance. Encapsulation of the rhenium 

substances (first component) into lipid coating is effective as in form of liposomes, as in form of 

nanoparticles; the Re-Pt system is effective in the form of nanoliposomes with mixed composition 

inside (encapsulation of both components) that opens great opportunities to use medicines with 

different properties and in ratio of personal inquire in one preparation. Elaboration of solid 

nanoparticles formulations of the Re-Pt requires additional investigations as on this stage of 

development of the idea it is clear that only one component of the system may be effectively included 

into solid lipid coating. Encapsulation of both components is promising, but requires additional 

procedures warranting prevention of the interactions between cisPt and rhenium compounds. 

Encapsulation of the Re-Pt antitumor system in nanoparticles and nanoliposomes resulted in active 

antyhemolytic properties of the systems and activated the specific antioxidant defence. 

References 

1. (a) N. Shtemenko, P. Collery, A. Shtemenko. Anticancer Res. 2007, 27, 2487-2492. (b) A. 

Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, et al. Dalton Trans. 2009, 26, 5132 - 5136. 

2. (a) C. Medina, M.J Santos-Martinez, A. Radomski. British Journal of Pharmacology, 2007, 150, 

552-558. (b) K. N. J. Burger, R.W. H. M. Staffhorst. Nat. Med., 2002, 8, 81-84. 

27

OP-12 


The [CpM(CO)3] - Moiety (M = Mn, Tc, Re) as Phenyl Ring analog – a Promising 

Strategy Towards New Drugs and Radiopharmaceuticals 

D. Can, H.P. N'Dongo, P. Schmutz and R. Alberto* 

University of Zurich, Faculty of Inorganic Chemistry, Winterthurerstrasse 190, 8057 Zurich, 

Switzerland. 

E-mail: daniel.can@aci.uzh.ch 

Structural changes imposed on proteins or nucleic acids by metal cations such as Ca 2+ or Zn 2+ are 

essential for the initiation of biological processes. Organometallic complexes are comparably rare as 

structural recognition site in receptors, whereas exactly this is how most organic molecules and drugs 

tend to work 1 . 

As early as 1979 Hanzlik et al. studied the interaction of �-Ferrocenylalanine with phenylalanine 

hydroxylase and phenylalanine decarboxylase and showed that the ferrocene derivative behaved like 

phenylalanine analogues 2 . Ongoing investigations by Jaouen et al. showed years later, that substitution 

of a phenyl ring in tamoxifen by ferrocene similarly kept the biological activity of the lead compound 

intact 3 . 

As 99m Tc is nowadays in the focus of the development of radiotracers, introducing group 7 transition 

metals as [CpM(CO)3] into this analogy opens new directions not only towards new drugs but also 

towards very promising radiopharmaceuticals. 

O 

N 

H 

Following this strategy we will present the analogy of different classes of bioactive compounds 

containing [CpRe(CO)3]: sulphonamides acting as carbonic anhydrase inhibitors with high binding 

affinities 5 , histone deacetylase inhibitors, amino acids transported by the LAT1 transporter and 

melanoma imaging agents with melanin afiinity. 

Herein we describe the synthesis and characterization of "cold" Re-compounds as surrogates to well 

known pharmaceuticals and discuss their analogy. For the "hot" molecules, we followed a general 

aqueous approach towards 99m Tc(CO)3 labeled � 5 -Cp derivatives from their dimeric Cp species via 

metal mediated retro-Diels-Alder reaction 4 and show that the conditions used can be applied to a 

variety of functional groups. 

References 

N 

OC 

Re 

O 

CO 

CO 

N 

H 

N 

1. S. J. Lippard, J. M. Berg, Principles of Bioinorganic Chemistry, University Science Books, Mill 

Valley, CA, 1994 

2. R. P. Hanzlik, P. Soine, W. H. Soine, J. Med. Chem., 1979, 22, 424-428 

3. G. Jaouen, S. Top, A. Vessière, Bioorganometallics, Wiley-VCH, Weinheim, 2006, p. 65 

4. Y. Liu, B. Spingler, P. Schmutz et al, J. Am. Chem. Soc., 2008, 130, 1554-1555 

5. C. T. Supuran, Nature, 2008, 7, 168-181 

28

OP-13 


Ferrocenyl Flavonoids: Synthesis and Antiproliferative Effects 

Elizabeth A. Hillard, a Jean-Philippe Monserrat, a Guy Chabot, b Louis Hamon, c and Gérard Jaouen c 

a Chimie ParisTech (Ecole Nationale Supérieure de Chimie de Paris), Laboratoire Charles Friedel, 

UMR CNRS 7223, 11 rue Pierre et Marie Curie, 75231 Paris cedex 05, France. b Chimie ParisTech 

(Ecole Nationale Supérieure de Chimie de Paris), Département Friedel; Université Paris Descartes, 

Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Pharmacologie Chimique, 

Génétique et Imagerie (CNRS UMR 8151- INSERM U 1022), 4 avenue de l’Observatoire, 75006 

Paris, France. c Institut Parisien de Chimie Moléculaire, UMR CNRS 7201, Université Pierre et Marie 

Curie, CC47, 4 Place Jussieu, 75252 Paris Cedex 05, France. 

Flavonoids, such as flavanones and flavones, are ubiquitous plant-based polyphenols. Their 

importance in health was first reported in 1936, 1 and numerous benefits have been reported for various 

conditions including cancer, cardio-vascular diseases, asthma, and viral infections Several pathways 

for chemoprevention have been elucidated, particularly protective antioxidant properties. However, 

some flavonoids, such as quercetin, are also known to act as prooxidants because they can be 

metabolized to o-quinones and quinone methides that subsequently produce ROS, which have been 

proposed as a way to stimulate apoptosis in cancer cells. 2 Because of the dual antioxidant/prooxidant 

actions of flavonoids, we therefore became interested in modifying these compounds with redoxactive 

ferrocene and screening them against cancer cells. 

O 

chalcone 

O 

O 

aurone 

O 

O 

flavone 

O 

O 

flavanone 

29 

HO 

O 

O 

OH 

OH O 

quercetin 

Fe 

OH 

ferrocenyl chalcone 

It is remarkable, that, although ferrocenyl chalcones have been widely studied for over 50 years, 3 there 

is, to our knowledge, no report of the corresponding ferrocenyl flavones or flavanones. We have 

recently discovered a novel reaction which gives easy access to the first ferrocenyl flavones, via a 

ferricenium intermediate. 4 The ferrocenyl flavones, furthermore, isomerize under basic conditions to 

give access to a class of ferrocenyl aurones. We have also been able to graft ferrocene to the flavanone 

skeleton via an acid-catalyzed condensation reaction. The synthesis of these new compounds and 

preliminary in vitro antiproliferative results will be presented. 

References 

1. S. Rusznyak, A. Szent-Gyorgyi, Nature 1936, 138, 27. 

2. H. Pelicano, D. Carney, P. Huang, Drug Resist. Update 2004, 7, 97-110. 

3. C. R. Hauser, J. K. Lindsay, J. Org. Chem. 1957, 22, 482-485. 

4. J-P Monserrat, G. G. Chabot, L. Hamon, L. Quentin, D. Scherman, G. Jaouen, E. A. Hillard, Chem. 

Commun., 2010, in press. 

OH

OP-14 


Preclinical Development of Metal-Based Compounds: 

Set Up of a Plastic Mouse Model 

A. Bergamo, a V. Vidimar, a D. Gallo, a G. Chiaruttini, a and G. Sava *a,b 

a Callerio Foundation Onlus, via A. Fleming 22-31, 34127, Trieste, Italy. b University of Trieste, 

Faculty of Pharmacy, Department of Life Sciences, via L. Giorgieri 7, 34127, Trieste, Italy. 

E-mail: a.bergamor@callerio.org 

Nowadays the main goal of solid tumour chemotherapy is the treatment of metastases, primary cause 

of death in most of the cancerous diseases. 1,2 The anti-cancer drugs currently used in the clinic have 

only limited success: to achieve effective therapeutic approaches, selectivity should be improved and 

the new drugs should be designed to hit targets specific of metastatic cells. This work arises from the 

need to renew the screening’s system of the anti-tumour drugs employed for the treatment of solid 

tumour metastases, a field still lacking of a simple, handy, and easily controllable in vitro models to be 

used for evaluating and measuring specifically the potential anti-metastatic activity of active 

principles. This project would contribute to match this unmet need through a biotechnological device, 

born from the collaboration between the Callerio Foundation Onlus and the Department of Materials 

and Natural Resources of the University of Trieste, able to mimic some physio-pathological 

conditions, typical of the metastatic process. This system constitutes a “bridge” between the “classic in 

vitro study” and the “classic in vivo study”; in the device the tumour cells can migrate, through a 

microcircuit, from a well representing the primary tumour, to a well representing the target organ of 

metastases. The model we wish to validate is the metastasis from colo-rectal cancer, a great social 

impact disease in western countries, which prognosis and life time expectancy are mainly determined 

from the progression of the secondary tumours to the liver, and not from the primary tumour itself. 3 In 

order to recreate a metastatic colorectal tumour model, human colon adenocarcinoma HT-29 are 

chosen as invasive and malignant cells, human non-malignant colon epithelial cell line HCEC is used 

to mimic a normal colonic epithelial tissue, and immortalized human hepatocytes IHH to mimic the 

healthy hepatic tissue. The first issue of this study is to set up the optimal environment to simulate the 

physio-pathological process of metastatization and liver invasion through the development of a coculture 

system in which the three cell lines grow together. In parallel the effects of three reference 

drugs for the treatment of colorectal cancer (irinotecan, 5-fluorouracil and oxaliplatin), 4 are studied in 

the same system. The results of theses series of experiments, propaedeutic to the extension of the coculture 

model in the biotechnological device, will be presented. 

Acknowledgements 

This work was carried out within the framework of COST Action D39. 

References 

1. P. Cairns, Nat. Rev. Cancer 2006, 7, 531-543. 

2. http://www.nlm.nih.gov/medlineplus/cancer.html 

3. J.M. McLoughlin, E.H. Jensen, M. Malafa, Cancer Control 2006, 13, 32-41. 

4. M. Koopman, C.J. Punt, Eur. J. Cancer 2009, 45 Suppl. 1, 50-56. 

30

OP-15 


Arjunolic acid: The First Renewable-Nano Triterpenoid in Bioorganometallics 

Braja G. Bag, *a Partha P. Dey, a Rakhi Majumdar, a Shaishab K. Dinda, a and Shib S. Das a 

a Vidyasagar University, Department of Chemistry and Chemical Technolgy, Midnapore 721 102, 

India. E-mail: bgopalbag@yahoo.co.in 

Utilization of plant metabolites as renewables in various facets of bioorganic, bioorganometallic and 

organic chemistry research has become significant in recent years because such investigations aim at 

the development of sustainable chemical feedstocks. 1 Ferrocene moiety has been utilized in the design 

of peptide analogues, redox-responsive gelators, enhanced antimalarial drugs, etc. 2 However, inspite 

of the abundance of a large variety of triterpenoids, having nano-metric dimensions with varied 

lengths of rigid and flexible parts, 3 according to our knowledge, no ferroceno-triterpenoid has been 

reorted so far. Availability of arjunolic acid 1, extractable from the heavy wood of Terminalia Arjuna 

became the first choice for such investigations. 4 

Figure 1: (a) A redox-responsive organogel from ferrocenylidene arjunolic acid 2, (b) SEM image 

reveals self-assembled fibrillar network having fibers of nano-meter diameters, (c) TEM image of CdS 

nano-particles templated by self-assembled nano-fibers from arjunolic acid derivatives. 

The ferrocenylidene arjunolic acid 2, synthesized in one-step from arjunolic acid 1 and formylferrocene 

in high yield, self-assembled in various organic media to form soft solid-like materials 

(Figure 1a, Table 1). Scanning electron micrographs of the soft-solids showed fibrillar net-work 

structures having fibers of nano-metric dimensions (Figure 1b). 

Solvent State Conc. 

(g/100 mL) 

Toluene Gel 10 

o-Xylene Gel 9 

m-Xylene Gel 10 

p-Xylene Gel 10 

Table 1: Gelation Test Results of 2 

Detailed investigations on the self-assembly of arjunolic acid 

or its derivatives revealed that most of these derivatives selfassemble 

in aqueous or organic liquids leading to the 

formation of fibers of nano-metric diameters. 5,6 When H2S 

gas was diffused through a gel of an arjunolic acid derivative 

in ethanol saturated with Cd(OAc)2, then porous CdS 

nanoparticles templated by the self-assembled nano-fibers were formed (Figure 1c). Recent results 

from our laboratory will be presented describing various approaches towards bioorganometallic 

chemistry for the utilization triterpenoids. 

Acknowledgements: Financial assistance from AvH foundation Germany and DRDO India are 

gratefully acknowledged. 

References 

1. B.G. Bag, S.K. Dinda, Pure Appl. Chem. 2007, 79, 2031. 

2. (a) D.R. van Staveren , N. Metzler-Nolte, Chem. Rev. 2004, 104, 5931; (b) F. Dubar, G. Anquetin, 

B. Pradines, D. Dive, J. Khalife, C. Biot, J. Med. Chem. 2009, 52, 7954. 

3. B.G. Bag, C. Garai, R. Majumdar, unpublished results. 

4. B.G. Bag, P.P. Dey, S.K. Dinda, W.S. Sheldrick, I.M. Oppel, Beil. J. Org. Chem. 2008, 4, 24. 

5. B.G. Bag, S.K. Dinda, P.P. Dey, A.V. Mallia, R.G. Weiss, Langmuir 2009, 25, 8663. 

6. B.G. Bag, G.C. Maity, S.K. Dinda, Org. Lett. 2006, 8, 5457. 

31

OP-16 

Ru 

N 

Cl Cl 

N 

Ru 

Cl Cl 


Anticancer Activity of Multinuclear Ruthenium-Arene Complexes Coordinated 

to Dendritic Poly(propyleneimine) Scaffolds 

R 

R 

O 

N 

R 

Cl 

Ru Cl 

N 

N 

Ru Cl 

O 

Cl 

N 

R 

N 

R 

N 

Cl 

Cl 

N 

Ru 

N 

Cl 

Cl 

R 

Gregory S. Smith *a and P. Govender a 

a University of Cape Town, Faculty of Science, Department of Chemistry, 7701, Cape Town, 

South Africa. E-mail: Gregory.Smith@uct.ac.za 

Dendrimers have found potential as molecular tools in biological applications, especially as nanocarriers, 

diagnostic agents and as chemotherapeutics. 1-4 An advantage of using dendrimers is their 

multivalency, which leads to increased interaction between a dendrimer-drug conjugate and a target 

bearing multiple receptors, further improving the selectivity to cancer cells. Large macromolecules, 

like dendrimers, can also specifically target tumours by exploiting the ‘enhanced permeability and 

retention’ (EPR) effect, in which macromolecules can accumulate at the tumour site due to an increase 

in blood vessel permeability within diseased tissues compared to normal tissues. 5 

In this presentation, we report a series of multinuclear ruthenium-arene complexes based on first- and 

second-generation poly(propyleneimine) dendritic scaffolds (Fig. 1). Their cytotoxicity against the 

A2780 human ovarian cancer cell line will also be discussed. 

O 

N 

Ru 

N 

O 

N 

Cl Cl 

Ru 

N 

Cl Cl 

N 

Ru 

N 

32 

R 

R 

Cl Cl 

N Ru 

N 

R 

R 

N 

N Ru 

Cl Cl 

= 

N 

R 

R 

N 

Ru N 

N 

Cl Cl 

R 

N 

Ru N 

Cl Cl 

Fig. 1: Ruthenium-arene metallodendrimers based on a poly(propyleneimine) scaffold. 

References 

1. (a) U. Boas, J. B. Christensen, P. M. H. Heegaard: Dendrimers in Medicine and Biotechnology: 

New Molecular Tools, RSC Publishing (2006). (b) C. C. Lee, J. A. MacKay, J. M. J. Fréchet, F. C. 

Szoka, Nature Biotech. 2005, 23, 1517-1526. 

2. F. Aulenta, W. Hayes, S. Rannard, Eur. Polym. J. 2003, 39, 1741-1771 and references therein. 

3. J. B. Wolinsky, M. W. Grinstaff, Adv. Drug Deliv. Rev. 2008, 60, 1037-1055 and references therein. 

4. (a) A. Agarwal, S. Saraf, A. Asthana, U. Gupta, V. Gajbhiye, N. K. Jain, Int. J. Pharm. 2008, 350, 

3-13. (b) E. R. Gillies, J. M. J. Fréchet, Drug Discov. Today 2005, 10, 35- 43. 

5. D.F. Baban, L.W. Seymour, Adv. Drug Delivery Rev. 1998, 34, 109-119. 

4+ 

O 

O H

OP-17 


Biofunctionalization of a Generic Collagenous Triple Helix 

with the Integrin α2β1 Binding Site 

Stephan Niland, a Christoph Westerhausen, b Thilo Bracht, a Alletta Schmidt-Hederich, a Désirée Freund, a 

Stephan W. Schneider, c Matthias F. Schneider, d and Johannes A. Eble a 

a Goethe University Frankfurt, University Hospital, Center for Molecular Medicine, Department of 

Vascular Matrix Biology, Excellence Cluster Cardio-Pulmonary System, Theodor-Stern-Kai 7, 60590 

Frankfurt/Main, Germany. b University of Augsburg, Faculty of Mathematics and Natural Sciences, 

Department of Experimental Physics I, Universitaetsstrasse 1, 86135 Augsburg, Germany. 

c Heidelberg University, Mannheim University Hospital, Department of Experimental Dermatology, 

Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. d Boston University, Department of 

Mechanical Engineering, Biological Physics, 590 Commonwealth Avenue, MA 02215, Boston, USA. 

E-mail: niland@med.uni-frankfurt.de 

Integrin �� is a major collagen-binding receptor and widely distributed on different tissues. It plays 

essential roles in elementary cell functions such as adhesion morphology, migration, proliferation, 

gene activation, and differentiation. Therefore, it regulates various (patho)physiological situations, 

such as thrombosis, tumor infiltration, and metastasis. It plays an essential role in liver micrometastasis 

formation. 1 

Integrin �� recognizes triple-helical collagens, whose quaternary structure consists of three lefthanded 

polyproline-like chains supercoiled in a right-handed helix about a common axis, yielding a 

characteristic triple helical coiled-coil, which provides the framework for the integrin �� 

recognition motif (GFOGER)3. Due to these structural requirements, chemical imitation of triplehelical 

�� integrin recognition site is still a demanding feat. The aim of this study was to generate a 

recombinant mini-collagen with a single binding site for integrin �� and to use this collagenmimetic 

to characterize the role of integrin ��at both molecular and cellular level. Force 

spectroscopy was used to determine at the molecular level the binding of integrin ��to its triplehelical 

recognition motif (GFPGER)3. To define and disclose the role of integrin ��in cell biology, 

an integrin ��-specific and agonistic recombinant mini-collagen was used, as well as the snake 

venom-derived highly specific integrin �� antagonist rhodocetin. 2 

The strong binding of integrin ��to its ligand underlines its importance as cellular 

mechanotransducer. On a substratum biofunctionalized with integrin binding mini-collagen FC3, cells 

behave similar as on collagen I in terms of adhesion, spreading and migration. As recombinant minicollagen 

FC3 is unhydroxylated, and thus highly specific for integrin ��, this integrin is fully 

sufficient to induce this behaviour, while the participation of other collagen receptors is at most 

ancillary under this conditions. 3 

References 

1. F. Rosenow, R. Ossig, D. Thormeyer, P. Gasmann, K. Schlüter, G. Brunner, J. Haier, J.A. Eble, 

Neoplasia 2008, 10, 168-176. 

2. J.A. Eble, S. Niland, T. Bracht, M. Mormann, J. Peter-Katalinic, G. Pohlentz, J. Stetefeld, FASEB J. 

2009, 23, 2917-2927l. 

3. S. Niland, C. Westerhausen, S.W. Schneider, M.F. Schneider, J.A. Eble, submitted to Biochem J., 

Bio-functionalization of a generic collagenous triple helix with the �� integrin binding site allows 

molecular force measurements. 

33

OP-18 


Organometallic Anticancer Drugs: From Simple Structures to Rational Drug 

Design Based on a Mechanistic Approach 

Paul J. Dyson 

Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH 

1015 Lausanne, Switzerland. E-mail: paul.dyson@epfl.ch 

Organometallic chemistry has a strong tradition in the rational synthesis of compounds with 

specific functions, whatever the nature of the required function. But how is rational synthesis 

of organometallic pharmaceutical compounds currently achieved? The first part of the 

presentation will discuss the relevant issues by considering examples from the literature as 

well as from my own laboratory. 1 The presentation then continue with a focus on 

organometallic compounds based on the ruthenium(II)-arene unit developed in my laboratory 

that exhibit excellent in vivo anticancer activity and overcome certain limitations of presently 

used drugs. 2 The elements of the drug design process and the relevant known drug targets will 

be discussed. It will be shown that ligands with specific functions can be introduced into the 

drug structure in order to endow the compound with specific properties allowing the metal to 

perform a more classical role. 

One of the overriding features of the compounds discussed during the presentation is that 

targets other than DNA, i.e. enzyme and protein targets, are crucial for metal drugs, especially 

for the ruthenium(II)-arene drugs emanating from my laboratory, and evidence to support this 

notion will be provided. 

References 

1. C. G. Hartinger, P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391–401. 

2. W. H. Ang, L. J. Parker, A. De Luca, L. Juillerat-Jeanneret, C. J. Morton, M. Lo Bello, M. W. 

Parker, P. J. Dyson, Angew. Chem. Int. Ed., 2009, 48, 3854–3857. 

34

OP-19 


Biological Activity of Gold and Silver Bis(Phosphino)Hydrazine Complexes 

Frederik H. Kriel, *a and Judy Coates a 

a AuTEK Biomed, Mintek, Private Bag X3015, Randburg, 2125, South Africa. E-mail: 

erikk@mintek.co.za 

The anti-tumour potential of gold(I) phosphine complexes was first identified at the time when 

auranofin was shown to kill tumour cells in culture. This sparked the interest of Berners-Price et al. 1,2 

and led to the development of the bis-chelated gold(I) phosphine anti-tumour compound 

[Au(bis(diphenylphospino) ethane)2]Cl and later [Au(bis(di-2-pyridalphosphino)ethane)2]Cl. Clinical 

development of delocalised lipophilic cations has been hindered by severe toxicity, but several classes 

of these compounds have demonstrated a relationship between anti-tumour selectivity and lipophilichydrophilic 

balance. 1,2 

Following on the work done by Berners-Price et al.; a series of hydrazine-bridged ligands have been 

synthesised to modulate the lipophilic-hydrophilic balance of the resulting complexes. 3,4 These include 

the phenyl, p-methoxyphenyl and p-dimethylaminophenyl derivatives of the bis-phosphine. The main 

focus of the research is on the group 11 transition metals and corresponding gold and silver phosphine 

complexes. Here we describe the anti-tumour activity and NCI 60 cell line profile of these compounds. 


The authors would like to thank the University of Pretoria for use of their facilities. Prof. Connie 

Medlen, Dr. Gisella Joone and Mrs. Margo Nell for guidance. Prof. Denver Hendricks at the 

University of Cape Town for reviewing the work. National Research Fund for the funding for training. 

The NCI for the 60 cell line screen. AuTEK Biomed (Mintek and Harmony) for permission to publish 

the results and financial support. 

References 

1 S. J. Berners-Price, Chem. Aust., 2004, 71, 10. 

2 S. J. Berners-Price, P. J. Sadler, Struc. and Bond., 1988, 70, 27. 

3 V. S. Reddy, K. V. Katti, Inorg. Chem., 1994, 33, 2695. 

4 F. H. Kriel, M. Layh, H. M. Marques, J Coates, Ph.D. Thesis, University of the Witwatersrand, 

2007. 

35

OP-20 


DNA and Protein Binding, Cleavage and Anticancer Activity of Organometallic 

(M = Ru(II), Rh(III) and Ir(III)) Arene Complexes 

R. Loganathan, a S. Ramakrishnan, a P. Kumar, c D. S. Pandey, c A. Riyasdeen, b 

M. A. Akbarsha, b and Mallayan Palaniandavar* a 

a Centre for Bioinorganic Chemistry, School of Chemistry, b Department of Animal Science, 

Bharathidasan University, Tiruchirapalli 620 024, India. c Department of Chemistry, Facult of 

Science, Banaras Hindu University, Varanasi 221 005, India. 

E-mail: palanim51@yahoo.com 

The study of organometallic compounds as anticancer agents is receiving much attention now. These 

compounds can be tuned by using suitable chelating ligands to facilitate their uptake into the cells or 

for selectivity of reactions with DNA or proteins. However, the number of such studies is very limited. 

This is because of the low solubility and instability in water and poor uptake by the cells. The 

ruthenium complexes NAMI-A and KP1019, which show prominent anticancer activity, are currently 

in clinical trials for the treatment of metastasis and colorectal cancers, respectively. Very recently, we 

have shown that non-covalent interactions of certain water soluble Ru(II) complexes 1,2 with DNA 

enhances the cytotoxicity against several cancer cell lines. It is noteworthy that a family of 

ruthenium(II)–arene complexes developed by Sadler, and Dyson et al. exhibits high in vitro and in 

vivo anticancer activity. The titanocene dichloride has already completed phase II clinical trials and 

ferrocifen, which is a ferrocenyl derivative of tamoxifen, appears set to enter clinical trials soon. More 

recently, increasing interest has been focused on organometallic-arene compounds, which show 

excellent antiproliferative properties in vitro and in vivo. In this work a series of water soluble 

organometallic complexes of the type [{Ru(η 6 -arene)(L)Cl}](BF4)2 (arene = benzene; 1 and p-cymene; 

2) and [{(η 5 - C10Me5)M(L)Cl}](BF4)2, (M = Rh; 3 and Ir; 4 and L = benzyl-di-pyridin-2-yl-amine) has 

been isolated and the structures of 3 and 4 have been determined by X-ray crystallography. The 

bidentate benzyl-di-pyridin-2-ylamine ligand is designed to provide hydrophobicity. Also, the present 

compounds are equipped with a chloride leaving group in order to enable covalent interaction of the 

complexes with biological targets. Further, the arene ligand provides hydrophobicity thus tuning the 

DNA- and protein-binding and DNA- and protein-cleaving properties of the complexes. The 

interactions of these metal complexes with CT DNA have been explored by using absorption, 

emission and CD spectroscopy and electrochemical and viscosity measurements. DNA and protein 

cleavage reactions have also been studied using agarose and polyacrylamide gel electrophoresis 

respectively. The anticancer activities and the mode of cell death have also been established. The 

results of our systematic investigations will be presented and discussed. 

References 

N3 

N2 

N1 

Cl 

Rh 

1. V. Rajendiran, M. Murali, E. Suresh, S. Sinha, K. Somasundaram, M. Palaniandavar Dalton Trans. 

2008, 148-163. 

2. V. Rajendiran, M. Murali, E. Suresh, M. Palaniandavar, V.S. Periasamy, M.A. Akbarsha 

Dalton Trans. 2008, 2157-2170. 

36 

N3 

N2 

N1 

Cl 

Ir

OP-21 


Organometallic Pyrone and Pyridone Complexes as Anticancer Agents 

Christian G. Hartinger, *a Wolfgang Kandioller, a Muhammad Hanif, a Andrea Kurzwernhart, a 

Helena Henke, a Robert Trondl, a Caroline Bartel, a Gerhard Mühlgassner, a Michael A. Jakupec, a 

Maria G. Mendoza-Ferri, a Alexey A. Nazarov, a,b Bernhard K. Keppler a 

a University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, Austria. 

b Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 

CH-1015 Lausanne, Switzerland. E-mail: christian.hartinger@univie.ac.at 

Organometallic compounds have received growing interest as potential chemotherapeutics for the 

treatment of cancer. Ru(II) compounds bearing ligands such as 1,3,5-triaza-7-phosphaadamantane, 

ethylene-1,2-diamine or maltol-derived ligands have shown promising anticancer properties with in 

vitro or in vivo anticancer activity comparable to or in some cases superior to cisplatin. 1 Some of the 

compounds are even active in cisplatin-resistant cell lines, probably due to different modes of action, 

and potentially provide a means to overcome drug resistance. 2 

Organometallic Ru–arene compounds bearing a maltol ligand were shown to be nearly inactive in 

vitro. 3 In order to study their biological properties, compounds with different substitution pattern [e.g. 

3-hydroxy-2-pyr(id)one vs. 3-hydroxy-4-pyr(id)one] of the pyrone-derived ligands were prepared, or 

an oxygen donor of the chelating moiety was replaced by sulphur. Furthermore, polynuclear 

compounds were obtained by linking pyridone moieties via aliphatic chains. The chemical properties 

of the obtained compounds are very different from that of the parent maltolato complex with regard to 

stability in aqueous solution, lipophilicity and, depending on the metal centre, reactivity with 

biomolecules. For example, reactions with amino acids demonstrate higher stability of thiopyrone than 

of pyrone complexes, which may explain their activity against human tumour cells. In general, the 

compounds show affinity to nucleobases, but the polynuclear compounds form extremely rare types of 

DNA and protein adducts and are efficient cross-linkers. 4 Anticancer potencies of the arene complexes 

are as divergent as their chemical behaviour, from compounds active in the low μM range to inactive 

compounds. Based on the chemical and biological data, structure-activity relationships have been 

elucidated, and further directions of development will be discussed. 

References 

1. G. Süss-Fink, Dalton Transactions 2010, 1673-1688. 

2. (a) W. H Ang, P. J. Dyson, Eur. J. Inorg. Chem. 2006, 4003-4018. (b) A. F. A. Peacock, P. J. 

Sadler, Chem. Asian J. 2008, 3, 1890-1899. 

3. A. F. A. Peacock, M. Melchart, R. J. Deeth, A. Habtemariam, S. Parsons, P. J. Sadler, Chem. Eur. J. 

2007, 13, 2601-2613. 

4. O. Nováková, A. A. Nazarov, C. G. Hartinger, B. K. Keppler, V. Brabec, Biochem. Pharmacol. 

2009, 77, 364-374. 

37

OP-22 


Metalloenzymes in the bacterial life on carbon monoxide: 

A view from structural biology 

Holger Dobbek,* and Jae-Hun Jeoung 

Humboldt-Universität zu Berlin, Institute of Biology, Structural Biology/Biochemistry, Unter den 

Linden 6, 10099, Berlin, Germany. E-mail: holger.dobbek@biologie.hu-berlin.de 

The biological conversions of small substrates like N2, H2, and CO2 are vital for the biogeochemical 

cycle and are typically catalyzed by metalloenzymes with complex iron-sulfur clusters. However, only 

little is known about how these metalloclusters activate their substrates. 

Carbon monoxide dehydrogenases (CODHases) catalyze the reversible oxidation of carbon monoxide 

with water, to carbon dioxide, two protons and two electrons. Two principal types of CODHases have 

been described, which differ in activity, metal composition, amino acid sequence and stability in the 

presence of oxygen. The Ni, Fe-containing CODHases found in anaerobic microorganisms have a 

unique Ni- and Fe-containing metal cluster called cluster C. 1 A Cu- and Mo-containing metal site is 

found in CODHases isolated from aerobic microorganisms. 1 

We used a crystallographic approach to gain further insights into the reaction mechanism of Ni, Fe- 

CODHases. Structural analysis of CODHII from Carboxydothermus hydrogenoformans in several 

different states showed how substrates are activated by cluster C. 2 Water is bound by an 

asymmetrically coordinated Fe(II)-ion and carbon dioxide has been shown to act as a bridging ligand 

between Ni and the Fe(II)-ion. Amino acids in the direct vicinity of the cluster may contribute to 

catalysis by fast proton transfers and the stabilization of negatively charged intermediates. We further 

tested the reactivity of cluster C with inhibitors 3 and slow substrates, whose binding mode was 

resolved at atomic resolution. The structural analysis of ligand binding to cluster C presents a 

complementary approach to spectroscopic methods describing the electronic changes of cluster C 

during catalysis. Both approaches converge to a mechanism in which substrate activation and catalysis 

is mediated by a binuclear Ni-Fe sub site of cluster C. 

References 

1. S. W. Ragsdale, Crit. Rev. Biochem. Mol. Biol. 2004, 39, 165-195. 

2. J.-H. Jeoung, H. Dobbek, Science 2007, 318, 1461-1464. 

3. J.-H. Jeoung, H. Dobbek, J. Am. Chem. Soc. 2009, 131, 9922-9923. 

38

OP-23 


Models for the Active Site in [FeFe] Hydrogenase with Silicon-containing Ligands 

Ulf-Peter Apfel, a Dennis Troegel, b Yvonne Halpin, c Stefanie Tschierlei, d Ute Uhlemann, d Helmar Görls, a 

Michael Schmitt, d Jürgen Popp, d P. Dunne, e M. Venkatesan, e Michael Coey, e,* Manfred Rudolph, a,* 

Johannes G. Vos, c,* Reinhold Tacke, b,* Wolfgang Weigand a,* 

a Institut für Anorganische und Analytische Chemie, Friedrich-Schiller-Universität Jena, August-Bebel- 

Straße 2, D-07743 Jena, Germany,wolfgang.weigand@uni-jena.de. b Institut für Anorganische Chemie, 

Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany. c Solar Energy Conversion SRC, 

School of Chemical Sciences, Dublin City University, Dublin 9, Ireland. d Institut für Physikalische 

Chemie, Friedrich-Schiller-Universität Jena, Helmholtzweg 4, D-07743 Jena, Germany. e SFI-Trinity 

Nanoscience Laboratory, Physics Department, Trinity College, Dublin 2, Ireland. 

A series of multifunctional (mercaptomethyl)silanes of the general formula type RnSi(CH2SH)4−n (n = 0–2; 

R = organyl) was synthesized, starting from the corresponding (chloromethyl)silanes. They were used as 

multidentate ligands for the conversion of dodecacarbonyltriiron, Fe3(CO)12, into iron carbonyl complexes 

in which the deprotonated (mercaptomethyl)silanes act as m-bridging ligands. These complexes can be 

regarded as models for the [FeFe] hydrogenase. They were characterized by elemental analyses (C, H, S), 

NMR studies ( 1 H, 13 C, 29 Si), and single-crystal X-ray diffraction. Their electrochemical properties were 

investigated by cyclic voltammetry to disclose a new mechanism for the formation of dihydrogen 

catalyzed by these compounds, whereby one sulfur atom was protonated in the catalytic cycle. The 

reaction of the tridentate ligand MeSi(CH2SH)3 with Fe3(CO)12 yielded a tetranuclear cluster compound. A 

detailed investigation by X-ray diffraction, electrochemical, Raman, Mössbauer, and susceptibility 

techniques indicates that for this compound initially a [Fe2{MeSi(CH2S)2CH2SH}(CO)6] is formed. This 

dinuclear complex is however slowly transformed into the tetranuclear species 

[Fe4{MeSi(CH2S)3}2(CO)8]. 

39

OP-24 


DNA-Organometallic Hybrid Catalysts 

Andres Jäschke, * Pierre Fournier, a Michaela Caprioara, a and Matthias Höhne a 

a Heidelberg University, Institute of Pharmacy and Molecular Biotechnology, Im Neuenheimer Feld 

364, 69120 Heidelberg, Germany. E-mail: jaeschke@uni-hd.de 

Hybrid catalysis combines homogeneous chemical catalysts with biopolymers to develop selective 

catalysts for organic reactions. While proteins have been used as hosts for various transition metal 

complexes, 1 only few published examples are based on nucleic acids. 2 In these reports high 

stereoselectivities were obtained in Diels-Alder reactions, Michael additions and fluorinations, with 

DNA as sole source of chirality, but all these systems relied on Lewis acid catalysis by Cu II ions. Our 

goal is the application of DNA-conjugated transition metal complexes in organometallic catalysis, as 

this kind of catalysis is widespread among synthetically useful reactions. 

We recently presented DNA-based systems that use Ir I -diene chemistry to catalyze an allylic 

substitution in aqueous medium. 3 Towards this end, we covalently attach transition metal ligands, like 

phosphinoxazoline and diene ligands, to specific positions of oligonucleotides. 4 

Our approach is based on a modular design where a 19mer oligodeoxynucleotide carrying a transition 

metal ligand is combined with different DNA or RNA counterstrands, thereby forming perfect and 

imperfect duplexes that provide subtle changes in the environment of the metal center. The covalent 

attachment of the ligand guarantees its specific, reproducible positioning on nucleic acid structures. 

We demonstrate that catalysis occurs in the presence of DNA and its numerous functional groups, and 

that the structure of the DNA modulates the stereochemical outcome of the reaction. 3 

Recent work will be presented on the extension of our approach to other reactions, metals, and ligands, 

and about rational and combinatorial strategies for improvement of performance and stereoselectivity. 

References 

Iridium(I)-catalyzed allylic amination using DNA-based ligands 

1. (a) J. Steinreiber, T. R. Ward, Coord. Chem. Rev. 2008, 252, 751. (b) M. E. Wilson, G. M. 

Whitesides, J. Am. Chem. Soc. 1978, 100, 306. (c) M. T. Reetz, M. Rentzsch, A. Pletsch, M. Maywald, 

P. Maiwald, J. J. P. Peyralans, A. Maichele, Y. Fu, N. Jiao, F. Hollmann, R. Mondiere, A. Taglieber, 

Tetrahedron 2007, 63, 6404. (d) A. Pordea, M. Creus, J. Panek, C. Duboc, D. Mathis, M. Novic, T. R. 

Ward, J. Am. Chem. Soc. 2008, 130, 8085. 

2. (a) G. Roelfes, B. L. Feringa, Angew. Chem. Int. Ed. 2005, 44, 3230. (b) N. S. Oltra, G. Roelfes, 

Chem. Comm. 2008, 6039. (c) D. Coquière, Ben L. Feringa, G. Roelfes, Angew. Chem. Int. Ed. 2007, 

46, 9308. (d) N. Shibata, H. Yasui, S. Nakamura, T. Toru, Synlett 2007, 1153. 

3. P. Fournier, R. Fiammengo, A. Jäschke, Angew. Chem. Int. Ed. 2009, 48, 4226. 

4. M. Caprioara, R. Fiammengo, M. Engeser, A. Jäschke, Chem. Eur. J. 2007, 13, 2089. 

40

OP-25 


Construction of Organometalloenzymes 

Yoshihito Watanabe a 

a Nagoya University, Graduate School of Science, Department of Chemistry, Chikusa, 464-8602, 

Nagoya, Japan. E-mail: yoshi@nucc.cc.nagoya-u.ac.jp 

A variety of protein structures are employed in nature as frameworks for the deposition of metal 

cofactors to provide metalloenzymes. Very recently, we have designed a myoglobin mutant as a 

model for a substrate bound form of cytochrome P450 and site 

specific aromatic hydroxylation was found to proceed by a 

stochiometric amount of H 2 O 2 in a few seconds. 1 As an 

extension of our efforts for the construction of 

organometalloproteins, we have replaced the heme prosthetic 

group with a series of M(salophen) complexes, Rh(Phebox) (Fig 

1), and Cu complexes. 2 Instead of these small protein cavities, 

we have also employed a protein having a large cavity, i.e., apo- 

ferritin (apo-Fr). Ferritin is an iron storage protein and its apoform 

has been employed as nano-reactors. We have also 

prepared a zero-valent palladium cluster by chemical reduction 

of palladium ions in the apo-ferritin cage and examined its catalytic hydrogenation activity. The 

palladium clusters catalyzes size-selective olefin hydrogenation because substrates must penetrate into 

the ferritin cavity through the size restricted channels. 3 Through the Pd•apo-Feritin study, we have 

found that there are Pd ion binding sites in the apo-ferritin to capture as many as 300 Pd ions. Thus, 

we have examined crystal structures of apo-ferritin containing various amounts of Pd ions. The crystal 

structures of Pd•apo-Fr has been refined to 1.65Å resolution (Fig 2). 4 We have further found that 

Pd II (allyl) ion utilizes 

different binding sites 

bearing different 

coordination structures 

(Fig 3). The Pd(allyl)• 

apo-Fr composites show 

catalytic activities for the 

Suzuki coupling reaction 

as shown below. 5 

References 

1) T. D. Pfister, et al., J. Biol. Chem. 280, 12858 (2005). 2) M. Koshiyama, et al., J. Am. Chem. Soc. 

127, 6556 (2005). 3) M. Suzuki, et al., Angew. Chem. Int. Ed. 43, 2527 (2004). 4) T. Ueno, et al., J. 

Am. Chem. Soc. 131, 2094 (2009). 5) T. Ueno, et al., J. Am. Chem. Soc. 130, 10512 (2008). 

41 

Fig.1 Apo-Mb•Rh(Phebox) composite 

structure. 

Fig.2 The crystal structure of apo-Fr•Pd. Fig.3 The crystal structure of apo-Fr•Pd(allyl).

OP-26 


CO Releasing Properties of cis-trans-[Re II (CO)2Br2L2] n Complexes: A Feature 

Modulated by Ligand Variation for a True Chance at Medicinal Applications. 

Fabio Zobi* a and Alois Degonda a 

a University of Zürich, Institute of Inorganic Chemistry, Winterthurerstr. 190, CH-8057, Zürich, 

Switzerland. E-mail: fzobi@aci.uzh.ch 

In recent years carbon monoxide (CO) has been acknowledged as a fundamental small-molecule 

messenger in humans. 1 The tissue specific distribution of heme oxigenases and their action-derived 

CO have been linked to several effects. For example, carbon monoxide acts as a signaling molecule in 

the inducible defensive system against stressful stimuli. 1 It plays a fundamental role in the circulatory 

system by improving vasorelaxation and cardiac blood supply and it suppresses arteriosclerotic lesions 

associated with chronic graft rejection. 1,2 As the importance of CO is been increasingly recognized, 

there is a steadily growing interest in the in pharmacological and medicinal applications of CO. Direct 

inhalation of carbon monoxide has been viewed as a novel therapeutic approach but reports on 

tolerance to CO exposure are contradictory. 

An alternative approach to the administration of carbon monoxide is the use of CO-releasing 

molecules (CORMs). An obvious choice for CORMs are transition metal carbonyl complexes with 

one or more CO ligands. Several complexes have been evaluated to date, but the pioneering work of 

Motterlini and Mann has resulted in the discovery of the fac-[RuCl(glycinato)(CO)3] complex 

(CORM-3) as the most promising compound for the CO release in vivo. 3 

In here we show that complexes of the type cis-trans-[Re II (CO)2Br2L2] n (where L = monodentate 

ligand) 4 act as CO-releasing molecules and that under physiologically relevant conditions the rate of 

CO release is comparable to that of CORM-3. The complexes represent a first example of metal-based 

CORMs in which the central metal ion is not found in a d 6 or d 8 configuration. The open shell d 5 

configuration of the Re system herein described represents an advantage over the more robust d 6 or d 8 

systems for which physical stimuli (e.g. UV radiation) are often needed in order to elicit dissociation 

of carbon monoxide from the metal core. The rate of CO release of cis-trans-[Re II (CO)2Br2L2] n 

complexes is pH dependent and can be modulated by ligand variation. These features offer a true 

chance for the application of these molecules in medicinal chemistry. 

References 

1. Wu, L.; Wang, R., Pharmacol. Rev. 2005, 57, 585-630. 

2. Otterbein, L. E.; Zuckerbraun, B. S.; Haga, M.; Liu, F.; Song, R. P.; Usheva, A.; Stachulak, C.; 

Bodyak, N.; Smith, R. N.; Csizmadia, E.; Tyagi, S.; Akamatsu, Y.; Flavell, R. J.; Billiar, T. R.; Tzeng, 

E.; Bach, F. H.; Choi, A. M. K.; Soares, M. P., Nature Med. 2003, 9, 183-190. 

3. Foresti, R.; Bani-Hani, M. G.; Motterlini, R., Intensive Care Med. 2008, 34, 649-658. 

4. Zobi, F.; Kromer, L.; Spingler, B.; Alberto, R., Inorg. Chem. 2009, 48, 8965-8970. 

42

OP-27 


Nitric Oxide Synthase Targeting with 99m Tc(I)/Re(I) Complexes 

João D. G. Correia,* a Bruno L. Oliveira, a Filipa Mendes, a Paula D. Raposinho, a Isabel Santos, a 

António Ferreira, b Carlos Cordeiro, b Ana P. Freire b 

a ITN, Unidade de Ciências Químicas e Radiofarmacêuticas, Estrada Nacional 10, 2686-953 

Sacavém, Portugal. b Universidade de Lisboa, Faculdade de Ciências, Departamento de Química e 

Bioquímica, Lisbon, Portugal. E-mail: jgalamba@itn.pt 

Nitric oxide (NO), a key signaling mammalian mediator in several physiophatolological processes, is 

biosynthesized in vivo by oxidation of L-arginine to L-citrulline catalalyzed by Nitric Oxide Synthase 

(NOS). 1 This enzyme has two constitutive isoforms (neuronal, nNOS; endothelial, eNOS) and one 

inducible isoform (iNOS). Noninvasive imaging of NOS expression in vivo by nuclear techniques, 

namely by Single Photon Emission Tomography (SPECT) or Positron Emission Tomography (PET), 

holds great potential for providing new insights in understanding NO/NOS-related diseases, and may 

facilitate the development of novel therapeutic approaches. 2,3 Aiming to find 99m Tc(CO)3-based tracers 

for probing NOS levels in vivo, we will report on the synthesis and characterization of novel 

Re(I)/ 99m Tc(I) organometallic complexes containing pendant bioactive units for recognition of NOS 

active site. 4 The enzymatic studies with isolated murine iNOS have shown that some Re(I) compounds 

could inhibit the enzyme, being the first examples of organometallic complexes able to inhibit NOS. 

Such effect was also observed in LPS-stimulated murine macrophages. Interestingly, a few complexes 

could also be used as NOS substrates by the same cell model. The biological assessment of the 99m Tccomplexes 

in different cell lines and in mice will also be presented. 

References 

1. S. Moncada, R. M. J. Palmer, E. A. Higgs, Pharmacol. Rev. 1991, 43, 109-142. 

2. D. Zhou, H. Lee, J. M. Rothfuss, D. L. Chen, D. E. Ponde, M. J. Welch,R. H. Mach, J. Med. 

Chem.2009, 52, 2443–2453. 

3. H. Hong, J. Sun, W. Cai, Free Radic. Biol. Med. 2009, 47, 684–698. 

4. B. L. Oliveira, J. D. G. Correia, P. D. Raposinho, I. Santos, A. Ferreira, C. Cordeiro, A. P. Freire, 

Dalton Trans. 2009, 1, 152-162. 


We thank the Fundação para a Ciência e Tecnologia (FCT) for financial support (POCI/SAU- 

FCF/58855/2004). Mallinkrodt-Tyco Inc. is acknowledged for providing the IsoLink® kits. B. L. O. 

thanks FCT for a BD grant (SFRH/BD/38753/2007). J. Marçalo is acknowledged for the ESI-MS 

analyses, which were run on a QITMS instrument (FCT Contract REDE/1503/REM/2005 - ITN). 

43

OP-28 


Mechanistic and Synthetic Studies of Bio-compatible 

Carbon Monoxide-Releasing Molecules 

Anthony J. Atkin, a Ian J. S. Fairlamb, a Jason M. Lynam, *a and Wei-Qiang Zhang a 

Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK 

E-mail: jml12@york.ac.uk 

Carbon monoxide – releasing molecules (CO-RMs) have become an exciting target for therapeutic 

intervention. 1 CO generated in mammals is responsible for a variety of important physiological 

functions and is a fundamental signalling mediator. CO gas also elicits a range of beneficial 

therapeutic effects, although the associated toxicity and inherent poor selectivity of CO in its naked 

form is clearly not ideal. The method of choice for taking advantage of the beneficial role of CO is to 

utilise a CO-RM, such as a metal carbonyl complex, which act as a source of CO in biological 

systems. 

Although the biological effects of CO (and CO-RMs) are now well established, there is little 

understanding of the precise requirements needed for transition metal carbonyl compounds to act as 

effective therapeutic agents. We have therefore undertaken a systematic study in order to elucidate the 

factors that may control CO-release. 2 This has allowed us to determine which metal-carbonyl scaffolds 

have the greatest potential to act as CO-RMs which has in turn informed a synthetic programme 

designed to prepare a library of novel complexes with bio-compatible ligands. For example, we have 

prepared a range of Group 6 compounds which contain both natural and non-natural amino acids 

incorporated into the coordination sphere of the metal through a range of binding modes (Figure 1). 

This presentation will detail the key results from the findings of our synthetic and mechanistic studies 

into the CO-release process, as well as the behaviour of the new bio-compatible CO-RMs. For 

example, we have demonstrated how the CO-release behaviour of the amino ester derivatives 1 may 

be simply modulated by the choice of the substituent on the organic ligand. A mechanistic study has 

demonstrated that this process is controlled by loss of the amino ester and therefore supply of the 

“M(CO)5” (M = Cr, Mo, W) fragment is crucial to CO-release in aqueous systems. For the CO-RMs 

with structure 2 the rate of CO-release correlates with the electrophilicity of the carbene carbon, 

consistent with a mechanism in which nucleophilic attack of water initiates the CO-release process. 

The scope of biologically-relevant ligands which can be introduced into the coordination sphere of the 

metal will also be detailed. 

References 

1. (a) T. T. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green, R. Motterlini, R. Angew. Chem. 

Int. Ed. 2003, 42, 3722-3729. (b) I. J. S. Fairlamb, A.-K. Duhme-Klair, J. M. Lynam, B. E. Moulton, 

C. T. O’Brien, P. Sawle, J. Hammad, R. Motterlini, Bioorg. & Med. Chem. Lett. 2006, 16, 995-998. 

(c) P. Sawle, J. Hammad, I. J. S. Fairlamb, B. E. Moulton, C. T. O'Brien, J. M. Lynam, A.-K. Duhme- 

Klair, R. Foresti, R. Motterlini, J. Pharmacol. Exp. Ther. 2006, 318, 403-410. (d) I. J. S. Fairlamb, J. 

M. Lynam, B. E. Moulton, I. E. Taylor, A. K. Duhme-Klair, P. Sawle, R. Motterlini, Dalton Trans. 

2007, 3603-3605. 

2. W.-Q. Zhang, A. J. Atkin, R. J. Thatcher, A. C. Whitwood, I. J. S. Fairlamb, J. M. Lynam, Dalton 

Trans. 2009, 4351-4358. 

44

OP-29 


Peptide-carbenes and peptide-phosphines transition metal catalysts for “Green” 

solid phase catalysts. 

Morten Meldal, *a Kasper Worm-Leonhard, a and Christian A. Christensen a 

a Carlsberg Laboratory, SPOCC-Centre, Gamle Carlsberg Vej 10, 2500 Valby, Denmark, 

E-mail: mpm@crc.dk 

In Nature metalloproteins play a crucial role in complex biochemical transformations while displaying 

exquisite regio- and enantio-selectivity. More importantly the protein framework coordinates the 

catalytic metal and ensure substrate match and lower activation energy of the reaction to provide very 

high turnovers, which in turn facilitates the efficient biochemical transformation at low concentration 

of the catalytic protein. 

These properties can advantageously be mimicked in the field peptide and peptide-organic chemistry 

to putatively create catalysts for “green” chemistry. By engineering the peptide scaffold with one or 

several ideal ligands for a variety of transition metals, e. g. Pd, Zn or Cu. artificial enzyme like 

compounds, displaying selectivity and turnover for general organic chemistry transformations may be 

obtained. 

This presentation describes the synthesis and application of carbene- and phosphine-precursors for 

incorporation into peptide frameworks that folds around a transition metal and forms relatively 

compact and stable globular structures with an enzyme like binding cavity for substrate binding and 

catalysis. The strategy is modular and well suited for a Split/Mix approach where a large number of 

catalysts may be generated in a single combinatorial synthesis. 

Backbone phosphinylated peptides (1) were synthesized on polar PEGA supports and in solution and 

the catalytic activity was compared. The solid supported catalysts were very efficient and could be 

recycled at least 5 times without loss of activity. The palladium coordination of the phosphine could 

furthermore be combined with folding and complexation with other dedicated functional groups in the 

peptide. 

Backbone carbenes (2) formed extremely stable palladium-peptido carbene complexes that did not 

loose any activity with time or use. These solid phase catalysts could be used in microwave assisted C- 

C and C-N couplings in water with good selectivities and quantitative yields. 

References 

1. (a) C. A. Christensen and M. Meldal. Efficient Solid-Phase Synthesis of Peptide Based 

Phosphine Ligands: Towards Combinatorial Libraries of Selective Transition Metal Catalysts. 

Chem. Eur. J. 2004, 11, 4121-4131; (b) C. A. Christensen and M. Meldal. Solid-phase 

synthesis of a P,S-ligand system designed for generation of combinatorial peptide-based 

catalyst libraries. J. Comb. Chem. 2007, 9, 79-85. 

2. (a) J. F. Jensen, K. Worm-Leonhard, and M. Meldal. Optically active (peptido-carbene) 

palladium complexes: towards true combinatorial solid phase libraries of transition metal 

catalysts. Eur. J. Org. Chem. 2008, 3785-3797 (b) K. Worm-Leonhard and M. Meldal. Green 

catalysts: Solid-phase peptide carbene ligands in aqueous transition metal catalysis. Eur. J. Org. 

Chem. 2008, 5244-5253. 

45

OP-30 


Construction of an Immunosensor via Copper-Free ‘Click’ Reaction Between 

Azido SAMs and Alkynyl Fischer Carbene Complex. Application to the detection 

of Staphyloccal Enterotoxin A 

Pratima Srivastava, a Amitabha Sarkar, b Sudeshna Sawoo, b Amarnath Chakraborty, b Pinak Dutta, b 

Othman Bouloussa, c Claire-Marie Pradier; d Souhir Boujday, d and Michelle Salmain *a 

a Ecole Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel (UMR CNRS 7223), 

11, rue Pierre et Marie Curie, 75231 Paris cedex 05, France. b Indian Association for the Cultivation 

of Sciences, Department of Organic Chemistry, 700032, Kolkata, India. c Institut Curie, laboratoire 

Physico-chimie Curie (UMR CNRS 168), 26 rue d’Ulm, 75248, Paris , cedex 05, France. d Université 

Pierre et Marie Curie, Laboratoire de réactivité de surface (UMR CNRS 7197), 4 place Jussieu, 

75252, Paris cedex 05, France. E-mail: pratima-srivastava@chimie-paristech.fr 

Keywords: Immunosensor, IRRAS, ‘click’ reaction, Fischer carbene, antibody-antigen reaction. 

A copper-free « click » reaction between azido-terminated self-assembled monolayers (SAMs) on gold 

and an alkynyl Fischer carbene complex yielded functionalized surfaces on which facile and swift 

grafting of amine-containing molecules was achieved via aminolysis of the Fischer carbene moieties 

(Figure). 1 

S 

+ 

N3 N 

N N 

MeO 

W(CO) 5 

Ph 

NH2 Au Au S 

Au S 

OMe 

W(CO) 5 

46 

(OC) 5W 

This 3-step process could be conveniently monitored by Infrared Reflection-Absorption Spectroscopy 

(IRRAS). An extensive study of the different parameters involved in the covalent grafting of proteins 

on the Fischer carbene modified SAMs was carried out. As an application, an antibody against 

Staphylococcal Enterotoxin A (SEA) was immobilized onto gold chips so as to ultimately construct an 

optical immunosensor for the detection of this toxin in food samples. 

References 

1. S. Sawoo, P. Dutta, A. Chakraborty, R. Mukhopadhyay, O. Bouloussa, A. Sarkar, Chem. Commun. 

2008, 5957-5959. 

NH 

N 

N N 

Ph

OP-31 


Polypeptides Induced Self-Association and Emission Properties of 

Platinum(II) and Gold(I) Complexes 

Toshiyuki Moriuchi, *a Masahiro Yamada, a Kazuki Yoshii, a and Toshikazu Hirao a 

a Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 

Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: moriuchi@chem.eng.osaka-u.ac.jp 

Highly-ordered molecular assemblies are constructed in bio-systems to fulfill unique functions as 

observed in enzymes, receptors, etc. Introduction of functional complexes into highly-ordered 

biomolecules is considered to be a convenient approach to novel biomaterials, bio-inspired systems, 

etc. Recently, the field of bioorganometallic chemistry has drawn great attention and undergone rapid 

development. Conjuction of organometallic compounds with biomolecules such as peptides and 

nucleobases is envisioned to afford such bioconjugates. The non-covalent bond is a powerful tool in 

the construction of architectural molecular assemblies. We have already demonstrated the chirality 

organization of ferrocene-peptide bioconjugates to induce highly-ordered molecular assemblies. 1 

Poly-L-glutamic acid (P(Glu)) is known to exist in a �-helix form at around pH 4.3. The carboxyl 

groups of side chains are expected to assemble cationic metal complexes along the exterior of poly-Lglutamic 

acid through the electrostatic interactions. On the other hand, poly-L-Lysine (P(Lys)) exists 

as a random coil conformation at a neutral pH due to repulsion between positively charged side chains, 

and an �-helical conformation at above pH 10.6 due to the reduced charge on the side chains at a pH 

above the pKa (10.5). P(Lys) bearing multiple positively charged side chains is envisioned to serve as a 

polymeric spatially aligned scaffold for the aggregation of negatively charged metal complexes. From 

these points of view, we embarked upon the assembling and self-association of luminescent metal 

complexes spatially along the cationic or anionic polypeptides to form the luminescent aggregates. 

The cationic organoplatinum(II) complexes 

[Pt(trpy)C≡CR] + (trpy = 2,2',6',2''-terpyridine; R = Ph 

(PtH), PhC12H25 (PtC12)) were introduced into the anionic 

poly-L-glutamic acid (P(Glu)) through electrostatic 

interactions. An emission based on metal-metal-to-ligand 

charge transfer (MMLCT) transition was observed in the 

case of P(Glu)-PtC12. However, such synergistic effect 

was not observed in the case of P(Glu)-PtH. Poly-L- 

glutamic acid was found to serve as an efficient molecular scaffold, wherein the platinum(II) 

complexes might be accommodated. 

The assembling and self-association of anionic dicyanoaurate(I), [Au(CN)2] � , spatially around the 

cationic poly-L-Lysine (P(Lys)) through electrostatic interactions was also demonstrated to form the 

luminescent [Au(CN)2] � aggregates. 

References 

1. (a) Chem. Commun. 1998, 1963. (b) J. Organomet. Chem. 1999, 589, 50. (c) J. Am. Chem. Soc. 

2001, 123, 68. (d) Organometallics 2001, 20, 1008. (e) Organometallics 2001, 20, 3101. (f) J. 

Organomet. Chem. 2001, 637-639, 75. (g) Org. Lett. 2003, 5, 4285. (h) Org. Lett. 2005, 7, 5265. (i) 

Org. Lett. 2006, 8, 31-34. (j) Dalton Trans. 2009, 4286. 

47 

M M M M M 

M M M M M

OP-32 


Homogeneous and Bio-Catalysis in Concert: 

Hybrids of ECE-pincer Organometallics and Lipases 

Gerard van Koten *a 

a Organic Chemistry and Catalysis, Faculty of Science, Utrecht University, The Netherlands 

g.vankoten@uu.nl 

Bis-ortho-chelated aryl-metal complexes, the socalled ECE-pincer metal complexes, exist in great 

varieties. Several novel strategies for anchoring these ECE-pincer metal complexes to soluble and 

insoluble supports have been developed. Novel synthetic routes have been developed for the direct 

introduction of functional para-substituents onto the pre-formed ECE-pincer metal complexes. 1 This 

allows, for example the introduction of anionic tethers which can non-covalently bind the ECE-pincer 

metal complex to the core of multicationic core-shell dendrimers. 

Recently, we concentrated on the covalent anchoring of ECE-pincer metal complexes to proteins. 2 

This approach, involving the inhibitory activity of nitrophenyl phosphonate esters to the catalytic triad 

(serine, histidine and asparagine) of lipases, has great potential for future applications in the fields of 

protein structure elucidation (NMR, X-Ray, mass spectrometry), medicinal chemistry (biomarkers, 

MRI contrast agents, radiopharmaceuticals), biomaterials and catalysis (enantioselectivity, catalysis in 

aqueous media). Crystal structures of these novel ECE-pincer metal-lipase hybrids show in detail how 

the ECE-pincer metal unit is covalently attached to the enzyme. 3 The photophysical (biomarker), 

coordinative and catalytic (dynamic kinetic resolution) properties of these and related rutheniumlipase 

hybrid materials will be discussed. 

Fig 1. Structure in the solid state of the NCN-pincer platinum bromide-cutinase hybrid. 

References 

1. M.Gagliardo, D.J.M. Snelders et al., Angew. Chem. 2007, 46, 8558. 

2. C.A. Kruithof et al., Chem. Eur. J. 2005, 11, 6869. 

3. B. Wieczorek et al., Chem. Eur. J. 2009, 15, 4270. 

48

OP-33 


Chemo-Genetic Optimization of DNA Recognition by Metallodrugs using a 

Presenter Protein Strategy 

Jeremy M. Zimbron, a A. Sardo, a T. Heinisch, a,b T. Wohlschlager, c J. Gradinaru, d C. Massa, b 

T. Schirmer, *b Marc Creus, *a and Thomas R. Ward *a 

aUniversity of Basel, Department of Chemistry, Spitalstrasse 51, Basel 4056, Switzerland, b University 

of Basel, Biozentrum, Klingelbergstrasse 50/70, Basel 4056, Switzerland, c University of Neuchâtel, 

Institute of Chemistry, Avenue de Bellevaux 51, Neuchâtel 2009, Switzerland 

DNA is a privileged target of anticancer metallodrugs like cisplatin. However, such drugs often suffer 

from high toxicity and drug-resistance due to non-selective binding to other than oncogenic DNA. 1 

To increase selectivity of small molecule drugs for macromolecular targets, “surface borrowing” can 

be used to provide additional surface contacts via a presenter protein, which modulates the specificity 

and affinity of ligand–macromolecule interaction. 2 The use of bifunctional molecules based on biotinstreptavidin 

technology has been used for targeting RNA, in which a contribution for protein contacts 

to the anti-tobramycin RNA aptamer was suggested. 3 Inspired by these presenter protein strategies and 

our previous experience of enantioselective artificial metalloenzymes, 4 we synthesized a biotinylated 

metallodrug (compound 1, Fig.1) inspired on promising anticancer Ru(II) piano-stool complexes, 4 for 

incorporation into streptavidin (Sav). 

Here we shown that a supramolecular assembly of a drug with a presenter protein can modulate 

selectivity through provision of additional non-covalent interactions with the target that are not 

typically available to small molecule drugs, thus allowing selectivity toward macromolecules such as 

DNA telomeres. 

Fig.1 Presenter protein strategy for targeting telomeric DNA with ruthenium metallodrugs. 

References 

1. L. Kelland, Nat. Rev. Cancer 2007, 7, 573. 

2. R. Briesewitz, G. T. Ray, T. J. Wandless, G. R. Crabtree, Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 

1953. 

3. I. Harvey, P. Garneau, J. Pelletier, Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 1882. 

4. M. Creus, A. Pordea, T. Rossel, A. Sardo, C. Letondor, A. Ivanova, I. Letrong, R. E. Stenkamp, T. 

R. Ward, Angew. Chem. Int. Ed. 2008, 47, 1400. 

5. P. C. Bruijnincx, P. J. Sadler, Curr. Opin. Chem. Biol. 2008, 12, 197. 

49

OP-34 


RAPTA-T interacts with �1�1 integrin at the molecular level 

Alletta Schmidt-Hederich, a Michael Grössl, c Alessia Masi, b Alberta Bergamo, b Gianni Sava, b Paul J. 

Dyson, c and Johannes A. Eble *a 

a Goethe University of Frankfurt, Faculty of Medicine, Center for Molecular Medicine, Vascular 

Matrix Biology, Excellence Cluster CardioPulmonary System, Theodor-Stern-Kai 7, 60590 

Frankfurt/Main, Germany. b Callerio Foundation, Via Fleming 31, 34127 Trieste, Italy. c Ècole 

Polytechnique Fedèrale de Lausanne, Department of Chemistry and Chemical Engineering, 1015 

Lausanne, Switzerland. E-mail: Eble@med.uni-frankfurt.de 

Metal-based compounds, such as cisplatin and ruthenium complexes have been used as cytostatic 

drugs in cancer treatment. These compounds are generally thought to target DNA and hence interfere 

with the growth of highly proliferative tumor cells. However, recent experiments have suggested that 

ruthenium compounds, such as RAPTA-T, additionally affect cellular interactions with the 

extracellular matrix (ECM). Among cell adhesion molecules, integrins form a numerous and most 

versatile family. They bind to ECM proteins in a divalent cation-dependent manner and thus mediate 

cell-matrix interactions and regulate tissue-specific cell morphology, migration, cell survival and 

proliferation. Therefore, they play key roles in various physiological situations and diseases, such as 

tumor progression and metastasis. 

To analyse the effects of ruthenium-based compounds, in particular RAPTA-T, on integrins at both 

cellular and molecular level, we used cell attachment studies as well as cell-free protein interaction 

assays with recombinant human integrins. Moreover, a test system to determine the binding of metal 

organic compounds to integrins was established. 

At the cellular level, RAPTA-T affected cell adhesion especially to the basement membrane collagen 

IV and to fibronectin, which is mediated via the integrins �1�1 and �5�1, respectively. The isolated 

integrins were affected in their binding properties towards their cognate ligands, depending on the 

incubation time with RAPTA-T. Bioanalytical studies, such as gel filtration of �1�1 integrin with the 

ruthenium compound followed by an on-line detection of ruthenium by inductively coupled plasma 

mass spectrometry (ICP-MS), demonstrated that RAPTA-T binds to �1�1 integrin and alters its ability 

to form higher aggregates. In parallel, the binding activity of �1�1 integrin is compromised. 

Additional studies will be necessary in the future to elucidate the molecular mechanism. 

50

OP-35 


Advances in Organometallic Chemistry for the Preparation of Molecular Imaging 

and Therapy Agents 

John F. Valliant*, a,b Anika Louie, a Alla Darwish, a Michael Cooke, a Antonio Toppino, a Karin 

Stephenson, b Ryan Simms b 

a McMaster University, Faculty of Science, Department of Chemistry, 1280 Main St. West, L8S 4M1, 

Hamilton, Canada. b The Centre for Probe Development and Commercialization, McMaster 

University, BSB-B231, 1280 Main St. West, L8S 4K1, Hamilton, Canada. E-mail: 

valliant@mcmaster.ca 

Medical isotopes that are metallic in nature are playing an increasingly important role in modern 

nuclear medicine and basic biological research. 1 Delivering these radioisotopes to specific 

biochemical targets while minimizing non-specific binding requires the development of new 

prosthetic groups that form robust metal complexes in high yield under conditions that do not 

degrade or modify sensitive targeting vectors. These prosthetic groups or ligands must also be 

versatile with respect to how they are linked to targeting vectors and structurally modified in 

order to meet the lipophilicity needs of the agent under development. With these requirements in 

mind, organometallic complexes of Tc and Re are attractive platforms for developing new 

imaging and therapy agents in that inert complexes can be formed in high yield using an array of 

unique chelates and organometallic ligands. The work to be presented will include the 

development of isostructural Re and Tc complexes that can be imaged in vitro and in vivo using 

fluorescence microscopy and radioimaging methods respectively. 2 Complexes will include novel 

chelates for the [M(CO)3] + core, which can be labeled at room temperature and incorporated into 

peptide vectors as if they were natural amino acids. In addition, a new generation of isostructural 

organometallic probes derived from carboranes will be presented. New labeling strategies for 

tagging these molecules that go beyond conventional bulk solution methods will also be 

discussed. 

References 

1. R. Alberto, J. Organomet. Chem. 2004, 692, 1179-1186. 

2. K. Stephenson, S.R. Banerjee, T. Besanger, O.O. Sogbein, M.K. Levadala, N. McFarlane, J. 

Lemon, D. R. Boreham, K. P. Maresca, J. D. Brennan, J. W. Babich, J. Zubieta, J. F. Valliant, J. Am. 

Chem. Soc. 2004, 126, 8598-8599. 

51

OP-36 


Syntheses of New Isomeric Analogues of HYNIC for Evaluation 

as a Bifunctional Chelator for Technetium-99m 

Anica Dose, a L. K. Meszaros, b S. C. G. Biagini* a and P. J. Blower* b 

a University of Kent, Functional Materials Group, School of Physical Sciences, Canterbury CT2 7NH, 

UK. b Kings College London, Division of Imaging Sciences, Rayne Institute 4 th Floor Lambeth Wing, 

St. Thomas’ Hospital, London SE1 7EH, UK. E-mail: ad308@kent.ac.uk 

N 

N 

Tc 

N 

N 

N 

N Tc 

1 2 

Fig 1: possible monodentate 1 

and chelating 2 structures of Tc- 

HYNIC complex 

Introduction: Technetium, as a meta-stable isotope is extensively used in 

nuclear medicine. It is a transition metal of the 7 th subgroup with all formal 

oxidation states between -1 and +7 accessible and therefore possesses a large 

range of coordination structures. 1 Since the first use of radiolabelled 

antibodies with the bifunctional chelator 6-hydrazinonicotinamide (6-HYNIC) 

3, 2 the use of radiopeptides with the metastable isotope of technetium 99m Tc as 

an imaging agent for cancer cells has increased significantly until today. 3 

However, robust structural data for these conjugates is lacking. The HYNIC 

and 99m Tc coordinating sphere is still not fully determined and previous studies provide ambiguous 

results about the complex. 4 To radiolabel a peptide with HYNIC and 99m Tc also requires one or more 

co-ligands to fulfil the coordination sphere around the metal. Different co-ligands can have different 

effects on the homogeneity and stability of the complex and its biodistribution. Finally they are 

responsible for the formation of more than one end product. The latest results gives a clear insight that 

there is one chelating HYNIC per metal site and the oxidation state of Tc is formally +5. 5 The question 

as to which mode of the HYNIC coordination, monodentate 1 or chelating 2 is operating, remains 

uncertain. 

Aims: The aim of this project is to assess the specific binding of the complex between HYNIC and Tc, 

Tc and co-ligands and a further investigation of potential direct interactions between Tc and the 

peptide. 6 

Results: Isomeric HYNIC analogues 

4-7 were synthesised. These syntheses 

are related to the synthesis of 6- 

HYNIC-Boc. 2 The preparation of 

HYNIC-rhenium crystals, will provide 

new data about the binding structure 

and this will be followed by the 

preparation of analogous HYNIC-Tc 

HO O 

N 

HO O 

crystals. The novel synthesis of Fmoc-Lysine-NHS-2-HYNIC-Boc was also succesfully accomplished. 

This will allow for its use in solid phase peptide synthesis (SPPS) to synthesise the “nanogastrin” 

peptide [Lys(R)-Glu-Ala-Tyr-Gly-Trp-Met-Asp-PheNH2] where R= HYNIC, which binds to the 

CCK-2 receptor overexpressed on certain tumours. 7 

Further work will evaluate the new ligands for labelling with Tc-99m and investigate the structural 

chemistry of the rhenium and technetium-99m complexes. 

References 

1. U. Abram, R. Alberto, J. Braz. Chem. Soc. 2006, 17, 1486-1500. 

2. M. J. Abrams, M. Juweid, C. I. Tenkate, D. A. Schwartz, M. M. Hauser, F. E. Gaul, A. J. Fuccello, 

R. H. Rubin, H. W. Strauss, A. J. Fischman, J. Nucl. Med. 1990, 31, 2022-2028. 

3. M. L. Bowen, C. Orvig, Chem. Commun. 2008, 41, 5077-5091. 

4. L. K. Meszaros, A. Dose, S. C. G. Biagini, P. J. Blower, Inorg. Chim. Acta 2010, 

DOI:10.1016/j.ica.2010.01.009 

5. R. C. King, M. Surfraz, S. Biagini, P. J. Blower, S. J. Mather, Dalton Trans. 2007, 43, 4998-5007. 

6. M. Surfraz, R. King, S. J. Mather, S. Biagini, P. J. Blower, J. Inorg. Biochem. 2009, 107, 971-977. 

7. R. King, M. B. U. Surfraz, C. Finucane, S. C. G. Biagini, P. J. Blower, J. Nuc. Med. 2009, 50, 591- 

598. 

52 

N 

H 

N 

NH 2·HCl 

HCl·H 2N 

H 

N 

HO O 

HO O 

HO O 

HN 

HN 

N 

HN 

NH2·HCl NH2 3 4 5 6 7 

Fig 2: HYNIC analogues 

N 

Cl 

N 

H 

N 

NH 2·HCl 

NH 2·HCl

OP-37 


Fluorescent Conjugates Between Dinuclear Rhenium(I) Complexes and Peptide 

Nucleic Acids (PNA) for Cell imaging and DNA Targeting 

Emanuela Licandro, *a S. Maiorana, a C. Baldoli, b G. Prencipe, a E. Ferri, a D. Donghi, c M. Panigati, c 

G. D’Alfonso, c and L. D’Alfonso d 

a Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Venezian 21, 

I-20133, Milano, Italy. b Istituto di Scienze e Tecnologie Molecolari, C.N.R., Via C. Golgi 19, I-20133 

Milano, Italy. c Dipartimento di Chimica Inorganica, Metallorganica e Analitica, Università degli 

Studi di Milano, Via Venezian 21, I- 20133, Milano, Italy. d Dipartimento di Fisica, Università di 

Milano-Bicocca, P.za Scienze 6, I-20126 Milan. Italyo. 

E-mail: emanuela.licandro@unimi.it 

Peptide nucleic acids (PNA) are structural analogues of DNA, with pseudo-peptide backbone based on 

N-(2-aminoethyl)glycine, which show high binding affinity and specificity for the complementary 

DNA and RNA. 1 The conjugation of organometallic complexes to biomolecules finds applications 

both in diagnostic and therapeutic fields. The incorporation of Re(I) complexes into PNA, can offer a 

double advantage, due both to its radiochemical and photo-emitting properties. 

In this communication we describe the set up of the synthesis of new PNA-rhenium organometallic 

bioconjugates as luminescent compounds for DNA targeting. In particular, we utilized two novel 

rhenium complexes, namely [Re2(CO)6(�-Cl)2(�-4-COOH-pyridazine)] and Re2(CO)6(�-Cl)2(�-4- 

(CH2)3COOH-pyridazine)], belonging to a recently developed family of dimeric luminescent 

rhenium(I) complexes, 2 which were conjugated with the tymine PNA monomer and decamer. The 

second complex was prepared in order to check the influence of the n-propyl chain spacer on the 

lifetime and quantum yields of the emission of the PNA-rhenium bioconjugate. The most fluorescent 

Re-PNA conjugate also showed two photon absorption properties as assessed by “in cell” experiments, 

that revealed that it permeates the cell membrane, staining both the cytoplasm and the nucleus. 

Although more detailed experiments are needed, in order to establish the kinetics of the process and to 

set a lower limit to the sample concentration to be used, these preliminary results indicate that the Re- 

PNA conjugate is viable as a fluorophore for cell imaging. 

References 

1. Peptide Nucleic Acids; 2nd Ed.; P. E. Nielsen, Ed.; Horizon Bioscience: Norfolk, UK, 2004. 

2. D. Donghi, G. D’Alfonso, M. Mauro, M. Panigati, P. Mercandelli, A. Sironi, P. Mussini, L. 

D’Alfonso, Inorg. Chem. 2008, 47, 4243-4255. 

53

OP-38 


Design of Cyclometalated Iridium(III) Polypyridine Complexes as Luminescent 

Biological Labels and Probes 

Kenneth Kam-Wing Lo 

Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, 

Hong Kong, P. R. China. E-mail: bhkenlo@cityu.edu.hk 

Many cyclometalated iridium(III) polypyridine complexes exhibit intense and long-lived emission that 

is very sensitive to the molecular structures and local environments of the complexes. These 

interesting properties allow the complexes to serve as useful probes for various biological molecules 

including oligonucleotides, peptides, and proteins. We have attached amine- and sulfhydryl-specific 

reactive functional groups such as isothiocyanate, aldehyde, and iodoacetamide to cyclometalated 

iridium(III) polypyridine complexes of the type [Ir(N^C)2(N^N)] + to yield new luminescent labels for 

biomolecules. Additionally, we have designed related iridium(III) polypyridine complexes appended 

with various biological substrates including indole, �-estradiol, biotin, and lipids, and utilized the 

complexes as luminescent probes for indole-binding proteins, estrogen receptors, avidin, and lipidbinding 

proteins, respectively. Some of these complexes show interesting dual-emissive properties 

that enable the biological binding event to be reflected by a change of emission profiles of the probes. 

Furthermore, we have recently developed DNA-metallointercalators, dendrimers, and PEGylation 

reagents derived from luminescent iridium(III) polypyridine complexes. We have focused on the 

molecular design, photophysical properties, biomolecule-binding behavior, cytotoxicity, and cellularuptake 

characteristics of these luminescent probes. 

R 1 

R 1 

References 

C 

C 

N 

Ir 

N 

N 

N 

R2 

+ 

Emission Intensity (A. U.) 

500 550 600 650 700 750 

Wavelength / nm 

1. K. K.-W. Lo, K. Y. Zhang, C.-K. Chung, K. Y. Kwok, Chem. Eur. J. 2007, 13, 7110 – 7130. 

2. K. K.-W. Lo, P.-K. Lee, J. S.-Y. Lau, Organometallics 2008, 27, 2998 – 3006. 

3. K. K.-W. Lo, K. Y. Zhang, S.-K. Leung, M.-C. Tang, Angew. Chem. Int. Ed. 2008, 47, 2213 – 

2216. 

4. J. S.-Y. Lau, P.-K. Lee, K. H.-K. Tsang, C. H.-C. Ng, Y.-W. Lam, S.-H. Cheng, K. K.-W. Lo, 

Inorg. Chem. 2009, 48, 708 – 719. 

5. K. Y. Zhang, S. P.-Y. Li, N. Zhu, I. W.-S. Or, M. S.-H. Cheung, Y.-W. Lam, K. K.-W. Lo, Inorg. 

Chem. 2010, 49, 2530 – 2540. 

54 

+ ER�

OP-39 


Subcellular Imaging of a Re(CO)3 Complex by Photothermal Infrared 

Spectromicroscopy (PTIR). 

Anne Vessières, a Clotilde Policar, b Marie-Aude Plamont, a Sylvain Clède, b Alexandre Dazzi c 

a ENSCP, CNRS-UMR 7223, 11 rue P. et M. Curie, F-75231 Paris Cedex 05, France, b Département 

Chimie de l’ENS, CNRS-UMR 7203, 24 rue Lhomond, F-75231 Paris Cedex 05, c Laboratoire de 

Chimie Physique, CNRS-UMR 8000, Université Paris-Sud 11, F-91405 Orsay Cedex, 

E-mail: a-vessieres@chimie-paristech.fr 

The most widely developed techniques for bio-imaging are those based on fluorescence 

spectroscopy, however vibrational techniques including infra-red (IR) are also valuable. However, in 

classical optical microscopy, sub-micrometric resolutions are not attainable in the mid-IR-range, as the 

diffraction criterion imposes resolution higher than �/2 (i.e. 2.5 µM at 2000 cm -1 ) which is not well 

suited for intracellular mapping. To reach sub-micrometric resolution, near-field techniques are 

mandatory. Photothermal induced resonance (PTIR) is a cutting edge technique using a set-up recently 

patented by Dazzi et al., 1 coupling atomic force microscopy (AFM) and a tunable infrared laser to 

make spatially resolved absorption measurements in the IR-range. It has been successfully used to 

map a single air-dried E. coli cell by irradiation in the amide I and II bands. 2 The next challenge is the 

identification and localization of exogeneous diluted compounds inside single cells. The Re(CO)3 unit 

grafted to a hydroxy-tamoxifen-like molecule has been selected for this study as it is stable in 

biological environments and displays intense absorption in the 1850 – 2100 cm -1 region where 

biological samples are transparent. 

Figure : left: AFM-set up. middle: PTIR mapping at 1925 cm -1 of a single cell incubated 1h with 10 

µM of the Re(CO)3 complex (red = high concentration) right : spectromicroscopy at the nucleus 

We will present the results of the chemical imaging of this Re complex, inside a single cell, 

using PTIR. Cells are initially located on the surface of a ZnSe prism by using the AFM topology. 

Then the complex is localized thanks to its two characteristic �CO bands at 1925 and 2017 cm -1 . Cells 

showed an uneven distribution of the complex with one hot spot (red area on the picture above) and 

cold regions (blue zones). Interestingly, this location seems to correspond to cell nucleus located using 

irradiation at 1240 cm -1 (phosphate band) and 1650 cm -1 (amide I of proteins). In addition, a spectrum 

recorded inside the hot spot shows the two characteristic bands of the complex at 1925 and 2017 cm -1 , 

thus confirming its presence (right part of the figure). 

References 

1. A. Dazzi, M. Reading, P. Rui, K. Kjoller, Patent 2008, WO/2008/143817 A. B. Lastname, C. D. 

2. A. Dazzi, R. Prazeres, F. Glotin, J.-M. Ortega, Infrared Physics Techn. 2006, 49, 113. 

55

OP-40 


Dynamical Studies of Bioconjugated Luminescent Ruthenium Complexes in 

Lipid Vesicles 

Edward Rosenberg, a Ayesha Sharmin, a J. B. Alexander Ross a 

a Department of Chemistry and Biochemistry 

University of Montana, Missoula, MT 59812, USA Email: edward.rosenberg@mso.umt.edu 

A detailed analysis of the time-resolved anisotropy decay of the emission from luminescent molecules 

can provide useful information about molecular dynamics in a given media. To obtain such 

information, the excited-state lifetime must match the time scale of the process being examined and it 

is desirable that the time-zero emission anisotropy be in the range of 0.1 or greater. In our prior work, 

we designed a series of phosphorescent ruthenium complexes that have the longer lifetimes, higher 

quantum yields and the lower symmetry required for studying the dynamics of these probes in lipid 

vesicle bilayers. 1 Starting with the complexes [Ru(H)(trans-PPh3)2(dcbpy)CO][PF6] (1) and [Ru( 

dppene) (5-amino- phen)CO(TFA)][PF6] (2) (dcbpy = 4,4’-dicarboxy bipyridine, dppene = 1,2diphenylphosphino 

ethene, 5-amino phen = 5-amino phenanthroline, TFA = trifluoroacetic acid) we 

have used standard techniques to covalently conjugate these molecules to two and one phosphatidyl 

ethanolamine molecules, respectively. Complex 2 has also been conjugated to cholesterol via reaction 

with cholesterol chloroformate. Analyses of the anisotropy decay as a function of temperature from 

the conjugated probes in vesicles—made from both naturally occurring and synthetic lipids—reveal 

that the lipid conjugates are located within the lipid bilayer while the cholesterol conjugated complex 

is at the bilayer-water interface. The rotational correlation times for the complexes are responsive to 

the nature of the lipid vesicle used and analyses of this parameter allowed a detailed picture of the 

kinds of motions of the conjugated complex in the vesicle. The lipid conjugates with 1and 2 

incorporated into vesicles via extrusion through a size-selective membrane, showed an unexpected 

blue-shift in the emission spectra and a corresponding short excited-state lifetime in the range of 10 ns; 

the lifetimes in solvents are in the range of 0.1-2 �s. This unusual phenomenon will be discussed in 

terms of the properties of the excited states in the lipid vesicle environment in contrast to in bulk 

solvents. For comparison with complexes 1and 2, related complexes have been conjugated to lipids 

and cholesterol via the phosphine ligands, and their photophysical properties in lipid vesicles will also 

be presented 

References 

1. Ayesha Sharmin , Reuben C. Darlington , Kenneth I. Hardcastle, Mauro Ravera, Edward Rosenberg, 

J. B. Alexander Ross “Tuning Photophysical Properties with Ancillary Ligands in Ru(II) Mono- 

Diimine Complexes,” J. Organometal. Chem. 2009, 694, 988-1000. 

56

OP-41 


Multi-Organometallic-Containing Peptide Nucleic Acids: Preparation and 

Biological Applications 

Gilles Gasser, *a,b Antonio Pinto, b Sebastian Neuman b and Nils Metzler-Nolte *b 

a University of Zurich, Institute of Inorganic Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, 

Switzerland. E-mail: gilles.gasser@aci.uzh.ch; b Ruhr-University Bochum, Faculty of Chemistry and 

Biochemistry, Department of Bioinorganic Chemistry, Universitätstrasse 150, D-44780 Bochum, 

Germany. 

Peptide nucleic acids (PNAs) are non-natural nucleic acid analogues. Their neutral pseudopeptide 

backbone is made of N-(2-aminoethyl)glycine units which are ligated via a methylene carbonyl to the 

four nucleobases (Figure 1). 1 In comparison to double-stranded DNA (dsDNA), corresponding 

PNA•DNA hybrids are thermally more stable due to the missing electrostatic repulsion between the 

strands. Moreover, PNA is much more mismatch sensitive than DNA enabling sensitive and selective 

mismatches discrimination. All these favourable features led to application of PNAs in various 

research areas such as antisense and antigene therapies or biosensing. 

O 

HO P O 

O 

O 

Base 

O 

O 

P 

O 

O 

O 

Base 

O 

O 

P 

O 

O 

n 

O 

Base 

OH 

57 

HO 

O O 

N 

Base 

N 

H 

O O 

DNA PNA 

Figure 1. Structure comparison between DNA and PNA. 

N 

Base 

N 

H 

Base 

O 

O 

N 

NH2 In order to modify the intrinsic properties of PNAs or in order to add new functionalities and/or 

spectroscopic properties to PNA oligomers, organometallics have been synthetically attached to these 

non-natural DNA analogues. During this talk, we will present our recent advances on the preparation 

of multi-organometallic-containing PNA monomers and oligomers as well as their potential for 

biological purposes (see Figure 2 for an example of application of metal-containing PNAs). 2-6 

Figure 2. Re-containing PNA oligomer mediated the silencing of enhanced green fluorescent protein 

(eGFP) in HeLa-eGFP cells 48 h after cellular delivery by electroporation. (200 x magnification in all 

images) 

References 

1. P.E. Nielsen, P., M. Egholm, R.H. Berg, O. Buchardt, Science 1991, 254, 1497-1500 

2. G. Gasser, N. Hüsken, S.D. Köster and N. Metzler-Nolte, Chem. Comm. 2008, 3675-3677. 

3. N. Hüsken, G. Gasser, S.D. Köster and N. Metzler-Nolte, Bioconjugate Chem. 2009, 20, 1578–1586. 

4. G. Gasser, O. Brosch, A. Ewers, T. Weyhermüller and N. Metzler-Nolte, Dalton Trans. 2009, 4310- 

4317. 

5. A. Sosniak, G. Gasser and N. Metzler-Nolte, Org. Biomol. Chem. 2009, 7, 4992 – 5000. 

6. M. Patra, G. Gasser, D. Bobukhov, K. Merz, A.V. Shtemenko and N. Metzler-Nolte, 2010, submitted. 

n


Poster presentations 

58

P-01 


In Vitro and In Vivo Anti-tumor Activities of Five Coordinated Cyclometallated 

Organoplatinum(II) Complexes Containing Biphosphine Ligands 

Hamidreza Samouei, a Mehdi Rashidi,* a Q. Ping Dou, *b Michael Frezza, b Yan Xiao, b 

amd Frank W. Heinemann c 

a Chemistry Department, College of Sciences, Shiraz University, Shiraz 71454, Iran. b Department of 

Pathology, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, Detroit, 

USA. c Institut fuer Anorganische Chemie, Universitaet Erlangen-Nuernberg, Egerlandstrasse 1, D- 

91058 Erlangen, Germany. E-mail:samouei@gmail.com 

Ever since Rosenberg in late 1960s discovered the anti-tumor activity of cisdiamminedichloroplatinum(II), 

cis-[Pt(NH3)2Cl2] known as cisplatin, 1 many other Pt complexes have 

been designed, synthesized and tested in order to circumvent the cisplatin acquired resistance, side 

effects, toxicity and low water solubility in order to increase the efficacy of the drug. 2 Most platinum 

complexes being used as therapeutic agents usually contain amine (with at least one N-H bond) 

ligands, 3 but the analogous complexes containing phosphine ligands are not unusual in these kinds of 

applications. 3b,4 Many attempts have been made during the past 3 decades to synthesize new 

complexes of platinum and other transition metals (such as Ru) to overcome the difficulties associated 

with cisplatin. For example some cyclometallated Pt(II) complexes have recently been used as active 

cytotoxic anticancer drugs. 4,5 The use of phosphine ligands instead of amines has recently been 

envisaged, in particular because a large number of gold complexes containing phosphine ligands have 

successfully been used as therapeutic agents. 4,6 

In the present study, we report two novel cyclometallated Pt(II) complexes containing biphosphine 

ligands with unique structural features that are more potent than cisplatin in relation to their anti-tumor 

activity and have also been found to exhibit proteasome-inhibitory activities in vitro and in vivo. We 

also have suggested a potential relationship between the structure of the complexes and their cytotoxic 

effects. 

References 

1. B. Rosenberg, L. VanCamp, J.E. Trosko and V.H. Mansour, Nature 1969, 222, 385-386. 

2. K. S. Lovejoy, S. J. Lippard, Dalton Trans. 2009, 10651-10659. 

3. (a) P. J. Miguel, M. Roitzsch, L. Yin, P. M. Lax, L. Holland, O. Krizanovic, M. Lutterbeck, M. 

Schurmann, E. C. Fusch, B. Lippert, Dalton Trans. 2009, 10774-10786; (b) J.C. Shi, C.H. Yueng, 

D.X. Wu, Q.T. Liu, and B.S. Kang, Organomet. 1999, 18, 3796-3801. 

4. R. W.Y. Sun, D. Ma, E. L. M. Wong, C. M. Che, Dalton Trans. 2007, 4884-4892. 

5. T.Okada, I.M.El-Mehasseb, M.Kodaka,, T.Tomohiro, K.Okamoto, H.Okuno, J. Med. Chem. 2001, 

44, 4661-4667. 

6. (a) L. C. Eiter, N. W. Hall, C. S. Day,G. Saluta, G. L. Kucera, U. Bierbach, J. Med. Chem. 2009, 52, 

6519-6522; (b) C. P. Bagowski, Y. You, H. Scheffler, D. H. Vlecken, D. J. Schmitz, I. Ott, Dalton 

Trans, 2009, 10799-10805. 

59

P-02 


Degradation of Platinum-Based Anticancer Drugs by Thiosulfate Ions: 

an EXAFS Study 

Diane Bouvet- Muller, a A. Michalowicz, a S.Crauste-Manciet, b,c and K. Provost a 

a Institut de Chimie et des Matériaux Paris Est, ICMPE/SAX, UMR 7182 CNRS-Paris Est, 2 à 8 rue 

Henri Dunant, 94320 Thiais, France, b Laboratoire de Pharmacie Galénique, Université Paris V, 

75006 Paris, France, c Service de Pharmacie, CHI Poissy Saint Germain en Laye, 78105 Saint 

Germain en Laye, France. E-mail: muller@u-pec.fr 

Three platinum complexes are currently used worldwide: cisplatin, carboplatin and oxaliplatin. 1 

Cisplatin is the most common, and its reactivity has been widely studied. On the contrary, derivatives 

of carboplatin and oxaliplatin deserve to be structurally characterized in order to understand their 

mode of action and stability in solution. This study takes place in the work carried out by our group on 

the behavior of these platinum complexes in presence of various halogen and sulfur ligands. 2-4 

These drugs react rapidly with nucleophilic species in solution. Their degradation has two 

consequences: in vitro, it can compromise the stability of the drug in solution before administration; in 

vivo, the structural modification of these molecules can induce notable changes in their modes of 

action. Sulfur nucleophilic ligands are particularly interesting: 5 they play a major role in the 

detoxification of the drugs. Particularly, thiosulfate ions are used to prevent nephro- and ototoxicity. 6 

This study deals with the reaction of carboplatin and oxaliplatin with thiosulfate. For both drugs, the 

reaction products remain in solution. Thus we used X-ray absorption spectroscopy in order to 

characterize their structures. Spectra have been recorded for different reaction times (from one hour to 

one month) and for different drug/thiosulfate ratios (from 1/2 to 1/40). For a 1/2 ratio at one month of 

reaction, we observe the displacement of the carboxylate ligand for both drugs,and a strong similarity 

of the signal between 3 and 4 Å. This EXAFS signal can be used as a signature of the Pt-Thiosulfate 

binding, in order to model the complete reaction products structures in solution. 

On this basis, the spectral and structural evolution as a function of the reaction time on one hand and 

of the drug/thiosulfate ratio on the other hand are discussed. 

References 

1. L.R. Kelland, Nat. Rev. Cancer 2007, 7, 573-584. 

2. D.Bouvet, A. Michalowicz, S. Crauste-Manciet, D. Brossard, K. Provost. Inorg. Chem 2006, 

45, 3393-3398. 

3. D. Bouvet et al. J. Synchr. Rad. 2006, 13, 477-483. 

4. K. Provost et al. Biochimie 2009, 91, 1301-1306. 

5. J. Reedjik, Chem. Rev. 1999, 99, 2499-2510. 

6. D.J. Leitao, B.W. Blakley. Journal of Otolaryngology 2003, 32, 146-150. 

60

P-03 


Biological Activity of Enantiomeric Complexes [PtCl2L2] 

(L2 = Aromatic Bisphosphanes and Aromatic Diamines) 

Luca Gaviglio, a Sophie Bombard, b Marzia Bruna Gariboldi, c Elena Monti, c Elisabetta Gabano, a 

Mauro Ravera, a amd Domenico Osella a 


Viale Michel 11, 15121, Alessandria, Italy. b Université Paris Descartes, Laboratoire de Chimie et 

Biochimie Pharmacologiques et Toxicologiques, 45, Rue des Saints-Pères, 75006 Paris, France. 

c Department of Structural and Functional Biology, University of Insubria, Section of Pharmacology, 

Via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. E-mail: luca.gaviglio@mfn.unipmn.it 

Enantiomeric complexes of formula [PtCl2L2] (L2 = R-(+)- and S-(-)-BINAP, where BINAP = 2,2’bis(diphenylphosphane)-1,1’-binaphthyl, 

and R-(+)- and S-(-)-DABN, where DABN = 1,1'binaphthyl-2,2'-diamine, 

were tested for their cytotoxic activity against three cancer cell lines and for 

their ability to bind to the human telomeric sequence folded in the G-quadruplex structure. Similar 

experiments were carried out on prototypal complexes cisplatin and cis-[PtCl2(PPh3)2] for comparison. 

Pt-complexes containing phosphanes proved less cytotoxic against cancer cell lines and less likely to 

interact with the nucleobases of the G-quadruplex than those containing amines; in both cases the S-(- 

)-isomer was more active than the R-(+)-counterpart. More specifically, whereas all the platinum 

complexes were able to platinate the G–quadruplex structure from the human telomeric repeat, the 

extent and sites of platination depended on the nature of the ligands. Complexes containing (bulky) 

phosphanes interacted only with the adenines of the loops, while those containing the less sterically 

demanding amines interacted with adenines and some guanines of the G-quartet. 1 

References 

1. S. Bombard, M. B. Gariboldi, E. Monti, E. Gabano, L. Gaviglio, M. Ravera, D. Osella, J. Biol. 

Inorg. Chem., 2010, in press, doi: 10.1007/s00775-010-0648-8. 

61

P-04 


Organometallic Palladium(II) Complexes Containing Tridentate [C,N,S] 

Thiosemicarbazone Ligands: Synthesis, Structure and Antimalarial activity 

Prinessa Chellan, a Kelly Chibale, a,b and Gregory S. Smith *a 

a University of Cape Town, Faculty of Science, Department of Chemistry, Private Bag, Rondebosch 

7701, South Africa, b Institute of Infectious Disease and Molecular Medicine, University of Cape 

Town, Rondebosch 7701, South Africa. E-mail: prinessa.chellan@uct.ac.za 

Thiosemicarbazones (TSCs) are Schiff base type compounds that are noted for their pharmacological 

properties, particularly as antiparisital, 1 antibacterial 2 and antitumoral agents. 3 The antiplasmodial 

activity of thiosemicarbazones against Plasmodium falciparum strains has been reported. 4 However, 

reports on the use of thiosemicarbazone metal complexes as antimalarial agents are sparse. 

In this presentation, we report the synthesis, characterisation and antimalarial study of mono-, di- and 

tetrameric cyclopalladated [C,N,S] Pd(II) complexes prepared from two thiosemicarbazone ligands, 

3,4-dichloroacetophenone thiosemicarbazone (1, Scheme 1) and 3,4-dichloropropiophenone 

thiosemicarbazone (2), which have previously been screened for biological activity. 5 Attendant 

questions to be addressed in this presentation are, whether coordination of these compounds to 

palladium enhances their inhibitory effects and if the number of thiosemicarbazone Pd(II) complex 

moieties per molecule would increase antiplasmodial activity. 

References 

Cl 

Cl 

4 

3 

Scheme 1 

5 

2 

1 

R 

Cl 

Cl 

N 

Pd 

Cl 

Cl 

PPh 3 

4 

3 

PPh 3 / Acetone 

5: R = CH 3 

6: R = CH 2CH 3 

N NH 2 

S 

5 

2 

R 

R 

N 

H 

N NH 2 

6 

N 

N NH2 3: R = CH3 4: R = CH2CH3 1 

Pd S 

Cl 

R 

5 

62 

S 

K 2[PdCl 4] / EtOH-H 2O 

4 

6 

3 

N 

R.T. 

Cl 

N 

1 

2 

4 

P P / Acetone 

Pd 

S 

NH 2 

P 

1: R = CH 3 

2: R = CH 2CH 3 

P 

H 2N 

S 

P P = bis(diphenylphoshino)ferrocene (7 and 8); 

trans-bis(diphenylphosphino)ethylene (9 and 10); 

bis(diphenylphosphino)benzene (11 and 12) 

Pd 

N 

Cl 

N 

7, 9, 11: R = CH 3 

8, 10, 12: R = CH 2CH 3 

1. K. J. Duffy, A. N. Shaw, E. Delorme, S. B. Dillon, C. Erickson-Miller, L. Giampa, Y. Huang, R. M. Keenan, 

P. Lamb, N. Liu, S. G. Miller, A. T. Price, J. Rosen, H. Smith, K. J. Wiggall, L. Zhang and J. I. Luengo, J. 

Med. Chem. 2002, 45, 3573-3578. 

2. X. Du, C. Guo, E. Hansel, P.S. Doyle, C.R. Caffery, T.P. Holler, J. H. McKerrow and F.E. Cohen, J. Med. 

Chem. 2002, 45, 2695-2707. 

3. D. Kovala-Demertzi, M.A. Demertzis, E. Filou, A.A Pantazaki, P.N. Yadav, J.R. Miller, Y. Zheng and D.A. 

Kyriakidis, Biometals 2003, 16, 411-418. 

4. For example, A. Walcourt, M. Loyevsky, D. B. Lovejoy, V. R. Gordeuk and D. R. Richardson, Int. J. 

Biochem. Cell Biol. 2004, 36, 401-407. 

5. For example, N. Fujii, J. P. Mallari, E. J. Hansell, Z. Mackey, P. Doyle, Y. M. Zhou, J. Gut, P. J. Rosenthal, 

J. H. McKerrow and R. K. Guy, Bioorg. Med. Chem. Lett. 2005, 15, 121-123. 

R 

Cl

P-05 


Solid-State Synthesis of Peptide-Tethered Pt(IV) Complexes 

and Their Cytotoxic Properties 

Sergey Abramkin, a Markus Galanski, a and Bernhard Keppler *a 

a University of Vienna, Faculty of Chemistry, Department of Inorganic Chemistry, Währingerstrase 

42, 1090, Vienna, Austria. E-mail: sergey.abramkin@univie.ac.at 

Platinum-based drugs play an essential role in cancer treatment since the discovery of the anticancer 

drug cisplatin. Subsequent development of complexes resulted in three generations of drugs, the last 

one to be approved by the FDA was oxaliplatin. Side effects remain one of the main shortcomings of 

chemotherapy, arising from lack of specificity and inefficient cell entry. 

Short peptides can be used for targeting and transportation of drug molecules. They can change not 

only the basic parameters like lipophilicity or water solubility, but even more complex interactions of 

drugs with the microenvironment can be influenced. The axial ligands of Pt (IV) are the optimal site 

for derivatization: upon reduction they are cleaved from the prodrug, and the Pt(II) complex is 

released. 

Inefficient cell entry is the reason for higher dosage of drugs, however stimulated uptake will increase 

the amount of the drug, reaching the intracellular target. Cell-penetrating peptides can be used for 

intracellular delivery of Pt complexes; the TAT peptide is the best studied example of this group. 

Selectivity can be achieved using the peptides as delivery vectors. High expression of the GRP 

receptor in many tumors (prostate, lung, breast) makes it an interesting target for platinum conjugates. 

The short peptide bombesin was chosen for conjugation to Pt to investigate its influence on cytotoxic 

properties. 

H 2 

N 

N 

H 2 

O 

Pt 

O 

O 

O 

O 

O 

O 

O 

O 

O 

OH 

OH 

R 

R = TAT47-57(YGRKKRRQRRR) or Bombesin(QWAVGHLM) 

Solid-phase synthesis is a commonly used method for the preparation of peptides and their conjugates. 

Oxaliplatin was oxidized and two uncoordinated carboxyl groups were introduced, thereafter the 

complex was reacted with polymer-bound TAT and bombesin. Cleavage with TFA and purification 

afforded mono- and bisconjugates, characterized with ESI-MS, NMR and analytical HPLC. Synthesis 

and cytotoxic properties will be presented. 

The support of COST, the FWF, the FFG and the Austrian Council for Research and Technology 

Development is gratefully acknowledged. 

63 

H 2 

N 

N 

H 2 

O 

Pt 

O 

O 

O 

O 

O 

O 

O 

O 

O 

OH 

+ 

R 

H 2 

N 

N 

H 2 

O 

Pt 

O 

O 

O 

O 

O 

O 

O 

O 

O 

R 

R

P-06 


Response Profile of Cancer Cells to Cisplatin Treatment 

Hamed Alborzinia, a Pavlo Holenya a and Stefan Wölfl *a 

a Ruprecht-Karls-Universität Heidelberg, Institute of Pharmacy and Molecular Biotechnology, 

Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany 

E-mail: hamed.alborzinia@uni-heidelberg.de, wolfl@uni-hd.de 

The cell based sensor chip system BIONAS® 2500 offers the ability to measure three important 

parameters of cellular metabolism on line in living cell cultures: (i) glycolytic flux measured as pH 

change; (ii) cellular respiration (mitochondrial activity) measured as oxygen consumption; and (iii) 

cellular morphology, adhesion and membrane function measured as cellular impedance. These 

parameters are analyzed with metabolic sensor chips (SC1000) that feature the following analytical 

tools: (i) ion-sensitive field effect transistors (ISFETs) to record pH changes; (ii) oxygen electrodes to 

monitor oxygen consumption; and (iii) interdigitated electrode structures (IDES) to measure 

impedance under the cell layer. Cells are grown on the chip surface and all parameters are measured 

continuously with the electrodes on the chip surface. To work under stable conditions the medium is 

exchanged in short cycles with an automated fluidic system. 

We use this system to measure changes in cellular metabolism and morphology in response to 

treatment with cisplatin in different cell lines on line. Cisplatin treatment shows a well defined onset 

of change in acidification and impedance at about 7h and 10h respectively after treatment is started. At 

these time points we collected cells for further analysis of specific signalling pathways and gene 

expression. Protein phosphorylation of growth related signalling pathways was analyzed with a 

phosphoprotein ELISA micro array. Gene expression was analyzed using whole genome Affymetrix 

Gene Expression micro arrays. 

This work was in part supported by the BMBF (FKZ 01 EA 0509: “Nutrition.Net”) and the DFG 

Forschergruppe FOR630. 

64

P-07 


Development of Novel [Diarylsalene]- and [Salophene]platinum(II) Complexes 

as Cytotoxic Agents 

Maria Proetto a amd Ronald Gust *a 

a Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2 + 4, 14195 Berlin, Germany 

Breast cancer is the most common cancer in women. 1 Platinum-based drugs are widely used against 

various solid tumours, but they are inactive against breast cancer. 

In this project, new platinum analogues have been synthesized in an attempt to overcome this problem. 

The complexes were tested in vitro for growth inhibitory activity on both hormone dependent MCF-7 

(ER+) and hormone independent MDA-MB-231 (ER-) breast cancer cells to determine possible 

selective effects. 

Based on the experience of the coordination chemistry of Schiff base ligands with different metals, 

we chose diarylsalene and salophene as ligands and synthesized two types of platinum complexes 

(Figure 1). Variations of the substituents in the aromatic rings were made to evaluate their significance 

for the cytotoxic profile. In order to understand the mode of action of these [diarylsalene]platinum(II) 

and [salophene]platinum(II) complexes, they were tested in vitro for DNA-binding and DNAintercalation. 

R' 

R 

References 

N N 

Pt 

O O 

R 

R' 

Figure 1 

1. World Health Organization International Agency for Research on Cancer. "World Cancer Report" 

2003. 

2. R. Gust, I. Ott, D. Posselt, K. Sommer, J. Med. Chem. 2004, 47, 5837-5846. 

3. A. Hille, I. Ott, A. Kitanovic, I. Kitanovic, H. Alborzina, E. Lederer, S. Wölfl, N. Metzler-Nolte, S. 

Schäfer, W.S. Sheldrick, C. Bischof, U. Schatzschneider, R. Gust, J. Biol. Inorg. Chem. 2009, 14, 711- 

725. 

65 

R'' 

N N 

Pt 

O O 

[diarylsalene]Pt(II) complexes [salophene]Pt(II) complexes 

R''' 

R'' 

2, 3

P-08 


Following Investigations of Antiradical and Bioconjugative Properties of 

Cluster Rhenium Compounds 

Alexander V. Shtemenko, a Alexander A. Golichenko, a and Nataliia I. Shtemenko b 

a Department of Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin 

Ave. 8, Dnipropetrovs’k 49005, Ukraine., b Department of Biophysics and Biochemistry, 

Dnipropetrovs’k National University, 72 Gagarin avenue, Dnipropetrovs’k 49010, Ukraine, E-mail: 

shtemenko@ukr.net 

Antiradical and bioconjugative properties of the five structural types of cluster dirhenium(III) 

compounds with halide, carboxylate and phosphate ligands were described. Antiradical properties of 

these substances occurred by δ-component of quadruple Re-Re bond ( �2�� bonds ) and was welldetectable 

in electronic absorption spectra (EAS) due to ��* transition (20000 - 14000 cm -1 ). It has 

been shown that the binuclear cluster fragment Re2 6+ actively reacts with artificial radicals in vitro, 

however the rate of such interaction strongly depended from the ligand environment of the cluster 

Re2 6+ -centre. The reaction rate decreased with an increase of induction effects of alkyl groups in the 

carboxylic ligands. The mechanism of antiradical action of Re2 6+ -derivatives may be explained by the 

transition of an unpaired electron of a synthetic radical to a δ-orbital of the Re2 6+ fragment, thus 

decreasing the Re-Re bond order. Cluster rhenium compounds revealed their antiradical properties in 

the model of tumor growth. We consider that antiradical properties of the rhenium compounds may 

also play a leading role in their antitumor properties. Recent investigations showed that the antiradical 

properties of rhenium compounds in vivo depended from the structure of the compounds, but this 

dependence did not coincide with that obtained from the investigations with artificial radicals shown 

herein and was more complex due to multidirectional interactions in living cells. Presented data 

showed positive future prospects for Re2 6+ -substances applications as therapeutic agents due to their 

low toxicity and antiradical activity. 

Very important was the fact that EAS gave information about the quadruple rhenium - rhenium bond 

mode of substitution that was used in the bioconjugative investigations. Different structural types of 

Re2 6+ -derivatives had the characteristic absorption maxima, which position were dependent from the 

quantity of hyperconjugated cycles around Re2 6+ -centre. The effect of hyperconjugation is realized 

due to the interaction of the delocalized �-bond of �-carboxylic ligands group and the �-component 

of the Re-Re bond. Bidentate coordinated tetra-�-phosphates [Re2(HPO4)4(H2O)2] 2- and 

[Re2(HPO4)2(H2PO4)2(H2O)2] .. 4H2O had the δ→δ* absorption band in the area 15625 см -1 , that 

corresponded to the existence of two hyperconjugated cycles around Re2 6+ - centre. These facts were 

used by us to show what was happened to the quadruple bond during formation of liposomes and 

interactions with lipids. The mechanism of interaction between nucleic bases and rhenium(III) 

compounds was studied and another mechanism of the interactions in comparison with platinides was 

demonstrated. Some experiments with proteins were also discussed. Thus, quadruple Re-Re bond 

offers unique opportunities to study processes of bioconjugation. 

66

P-09 


Lead Structure Development of Cytotoxic ([9]aneS3)Rh(III) Compounds 

Containing Polypyridyl and Related Ligands 

Ruth Bieda, a Andreas Meyer, b Ingo Ott, b and William S. Sheldrick *a 

a Ruhr Universität Bochum, Faculty of Chemistry and Biochemistry, Department of Analytical 

Chemistry, Universitätsstraße 150, 44780 Bochum, Germany. b Technische Universität Braunschweig, 

Institute of Pharmaceutical Chemistry, Beethovenstraße 55 ,38106 Braunschweig, Germany. 

E-mail:ruth.bieda@rub.de 

Various compounds of the type [RhCl(LL)([9]aneS3)] 2+ (LL = bpy, bpm, phen, tap, dpq, dppz) 

containing the tridentate ligand [9]aneS3 were prepared with the goal of establishing structure-activity 

relationships with regard to their DNA interaction and cytotoxic activity. 1 Polypyridyl ligands of 

different size and length were used as well as diamine and thiaether ligands. Recently published data 

have revealed that rhodium(III) complexes containing polypyridyl ligands, which were previously well 

known for their intercalating DNA binding properties, also exhibit pronounced cytotoxic activity. 2 

For the determination of structure-activity relationships, modified ligands similar to 2,2’-bipyridine 

were also investigated. For instance, the organometallic compound containing the ligand 2phenylpyridine 

reduces the overall charge of the compounds to +1, a change that could lead to an 

improvement in the cellular uptake. The biological properties of this complex were compared with 

those of the analogous 2,2’-bipyridine and 2,2’- bipyrimidine compounds. 

Interactions of the cytotoxic ([9]aneS3)Rh(III) complexes with DNA were investigated by CD, UV/Vis 

and NMR spectroscopy and by gel electrophoresis. Peptide interaction due to covalent binding 

following chloride exchange were also established by ESI-MS. IC50 values toward the cancer cells 

MCF-7 and HT-29 as well as toward the human embryonic kidney cells HEK-293 were determined 

using the crystal violet assay. Apoptosis induction was ascertained for non-adherent BJAB lymphoma 

cells and healthy leukocytes. The studies indicate dramatic differences in cytotoxic activity and cell 

selectivity within the ligand series LL = bpm, bpy, 2-phenylpyridine. A very high cell selectivity 

towards malign lymphoma cells was established for LL = bpm. The complexes induce apoptosis by 

the intrinsic mitrochondrial pathway and cause negligible necrosis. 

References 

S 

S 

S 

Rh 

Cl 

N 

+ 2+ 

67 

Rh 

2-phenylpyridine 2,2’-bipyrimidine 

1. R. Bieda, I. Ott, M. Dobroschke, A. Prokop, R. Gust, W. S. Sheldrick, J. Inorg. Biochem. 2009, 

103, 698-708. 

2. (a) M. Harlos, I. Ott, R. Gust, H. Alborzinia, S. Wölfl, A. Kromm, W. S. Sheldrick, J. Med. Chem. 

2008, 51, 3924-3933. (b) R. Bieda, I. Ott, R. Gust, W. S. Sheldrick, Eur. J. Inorg. Chem. 2009, 3821- 

3831. 

S 

S 

S 

Cl 

N 

N 

N 

N

P-10 


Octahedral Ruthenium Complexes as Protein Kinase Inhibitors 

Sebastian Blanck a and Erik Meggers* a 

a Philipps-Universität Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35043 Marburg, 

Germany. E-mail: sebastian.blanck@chemie.uni-marburg.de 

Protein kinases are an important target in the field of medicinal chemistry. Since protein 

phosphorylation represents a key step in many crucial cellular processes, the synthesis of potent and 

selective kinase inhibitors has become more and more important. The ATP competitive 

indolocarbazole alkaloid staurosporine is a potent but rather unselective inhibitor. Meggers et al. have 

pioneered the design of inert and rigid organometallic complexes using staurosporine as a lead 

structure (Figure 1). 1 

Figure 1: Staurosporine as lead structure for octahedral metal complexes as kinase inhibitors. 

By varying the ligands A-D around the metal center the preference for certain kinases can be 

changed. 2 Thus it is possible to synthesize a variety of different kinase inhibitors using combinatorial 

chemistry. The octahedral complex 1 has been found to be a good inhibitor for the protein kinase 

GSK-3. GSK-3 has been shown to be a key component of the signal transduction in the insulin and 

wnt signalling pathways. 3 1 is significantly more potent for the α-isoform (IC50 = 8 nM) over the βisoform 

(IC50 = 50 nM), which is astonishing because GSK-3α and GSK-3β show 97% sequence 

identity in the ATP-binding pocket. By using molecular modeling and structure based drug design it 

was possible to increase the potency against GSK-3α by almost an order of magnitude (IC50 = 1 nM), 

while the isoform selectivity remained the same. The amino group of the complex is very important 

for the binding to the kinase since a protection of the functional group results in a complete loss of 

inhibition as in metal complex 3 (Figure 2). 

References 

Figure 2: 2-(Aminomethyl)pyridine complexes as kinase inhibitors. 

1. E. Meggers, G. E Atilla-Gokcumen, H. Bregman, Synlett 2007, 8, 1177. 

2. H. Bregman, P. J. Carroll, E. Meggers, J. Am. Chem. Soc. 2006, 128, 877. 

3. N. Pagano, J. Maksimoska, E. Meggers, Org. Biomol. Chem. 2007, 5, 1218 

68

P-11 


Synthesis, Characterizatiotion and Biological Evaluation of New Organometallic 

Rhenium(I) Complex with Ferulic Acid 

Dmytro Bobukhov, a Maksym Izumsky, a and Alexander Shtemenko *a 

a Ukrainian State Chemical Technological University, Department of Inorganic Chemistry, Gagarin 

Avenue 8, 49005, Dnipropetrovs’k, Ukraine. E-mail: dbobukhov@googlemail.com 

The aqueous chemistry of the organometallic cation [Re(CO)3(H2O)3] + has received much attention 

over the past decade, due to its relevance to the design of 186/188 Re radiopharmaceuticals as well as its 

ability to act as a surrogate for the chemistry of [ 99m Tc(CO)3] + . In many cases, these investigations 

have focused on reactions between biomolecules and [Re(CO)3(H2O)3] + . The attractiveness of this 

low-valent precursor results from its particularly high thermodynamic stability, that is, high 

substitution stability of CO ligands and substitution lability of water molecules, which can be easily 

replaced by a variety of mono, bis, and tridentate ligands of different size, shape, and donor atom sets. 1 

Here we report the synthesis, characterization and biological evaluation of new rhenium(I) complex 

with ferulic acid (3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid, C10H10O4). Ferulic acid is a 

phenolic acid of low toxicity, it can be absorbed and easily metabolized in the human body. Ferulic 

acid has been reported to have many physiological functions, including antioxidant, antiinflammatory, 

antithrombosis, and anticancer activities. 2 Because of these properties and its low 

toxicity, we decided to study interaction between trans-ferulic acid and [Re(CO)3(H2O)3] + cation, and 

possibility of using phenolic acid – rhenium(I) complexes in biomedicine. The corresponding complex 

was synthesized in a stepwise manner from [Re(CO)3(H2O)3]Br and trans-ferulic acid in methanol. 

The compound has been characterized by 1 H NMR, ESI-MS and IR spectroscopy. Crystal structure 

and biological activity of the corresponding complex will be discussed. 

References 

1. S. Alves, A. Paulo, J. D. G. Gorreia, L. Gano, C. J. Smith, T. J. Hoffman, I. Santos, Bioconjugate 

Chem. 2005, 16, 438-449. 

2. S. Ou, K.-C. Kwok, J. Sci. Food Agric. 2004, 84, 1261-1269. 

69

P-12 


Synthesis of Ferrocene Peptide Conjugates and their Application as Inhibitors of 

Peptide Association 

Samaneh Beheshti, a and Heinz-Bernhard Kraatz a 

a The University of Western Ontario, Faculty of Science, Department of Chemistry, 1151 Richmond St, 

N6A 5B7, London, Ontario, Canada. Email: sbehesh@uwo.ca 

The amyloid beta peptide (Aβ) with 40-42 amino acids is the major constituent of plaques found in 

the brain of people affected with Alzheimer’s disease. 1 There is a hypothesis that conformational 

switching from α-helical to β-sheet ultimately leads to amyloid fibril formation . On this basis, finding 

compounds that are able to destabilize the β-sheet structure and to interfere with the assembly of 

peptide strands is a useful strategy to prevent peptide aggregation and fibril formation. Synthetic 

peptides have been reported as β-sheet breakers that preclude amyloid formation. 2 For example, a 

novel pentapeptide inhibitor that has a proline in place of valine and an aspartic acid in place of 

alanine in the Aβ17-21 (Leu-Val-Phe-Phe-Ala) fragment has been reported with the ability to inhibit the 

formation of amyloid fibrils. 3 In this work, a series of Fc-peptide conjugates is prepared of the type 

FcCO-Val-Phe-Phe-OR (1:R = Me, 2:R = H), Fc[CO-Val-Phe-Phe-OR]2 (3:R = Me, 4:R = H), Fc[CO- 

Val-Phe-OR]2 (5:R = Me, 6:R = H) and Fc[CO-Leu-Val-OR]2 (7:R = Me, 8:R = H) . Conformational 

properties of these ferrocene peptide conjugates and their interaction with several sequences of Aβ 

have been studied in solution by circular dichroism and scanning electron microscopy. In addition, the 

interaction of Aβ attached on the gold surface with these ferrocene peptide conjugates has been 

studied by using electrochemical methods. 

References 

1. L. O. Tjernberg, J. Naslund, F. Lindqvist, J. Johansson, A.R. Karlstrom, J.Thyberg, L. Terenius,C. 

Nordstedt, J. Biol. Chem. 1996, 271, 8545-8548. 

2. C. Soto, E.M. Sigurdsson, L. Morelli, R.A. Kumar, E.M. Castano, B. Frangione, Nat. Med. 1998, 4, 

822-826. 

3. C. Adessi, M.J. Frossard, C. Boissard, S. Fraga, S. Bieler, T. Ruckle,F. Vilbois, S.M. Robinson, M. 

Mutters, W.A. Banks, C. Soto, J. Biol. Chem. 2003, 278, 13905-13911. 

70

P-13 


Synthesis, Characterization, and Biological Study of Functionalized 

Cyclopentadienylmanganese and Rhenium Tricarbonyl Complexes 

and Their Peptide Bioconjugates 

Wanning Hu, a Katrin Splith, b Ines Neundorf, b and Ulrich Schatzschneider *a 

a Ruhr-Universität Bochum, Lehrstuhl für Anorganische Chemie I - Bioanorganische Chemie, 

Universitätsstr. 150, D-44801 Bochum, Germany. 

b Institut für Biochemie, Universität Leipzig, Brüderstr. 34, D-04103 Leipzig, Germany. 

wanning.hu@rub.de 

rel. cell viability [%] 

125 

100 

75 

50 

25 

0 

0 50 100 150 200 250 

csubstance [�mol] 

Cym1-sC18 

Cyr1-sC18 

Cyr5-sC18 

71 

OC 

M 

CO CO 

O 

M = Mn, Re 

L 

COOH 

Several functionalized cyclopentadienyl manganese and rhenium tricarbonyl half-sandwich complexes 

were prepared and coupled to the sC18 carrier peptide to investigate whether the structural 

modification of the linker and the change of the metal center would influence the biological properties 

of the metal-peptide-bioconjugates. Two new cymantrene complexes with a 1,3- and 1,4-phenylene 

linker were prepared and were fully characterized with 1 H-NMR, 13 C-NMR, IR, ESI-MS, elemental 

analysis, and X-ray crystallography. 1 In addition, three novel related CpRe(CO)3 complexes showed 

good purity in 1 H-NMR, IR and ESI-MS. Four of the compounds were successfully coupled to the 

sC18 peptide and the cytotoxicity of the conjugates was studied with the resazurin assay on MCF-7 

human breast cancer cells. The CpMn(CO)3 conjugates showed IC50 values of about 55 µM on MCF-7 

human breast cancer cells, which is comparable to other cymantrene-sC18 conjugates already studied. 2 

In contrast, the rhenium analogue of the cymantrene complex with the 1,2-phenylene linker is inactive 

at up to 150 µM. However, a CpRe(CO)3 complex with the 1,4-phenylene linker but a methylene 

group between the Cp and phenyl rings gave a bioconjugate with an activity very similar to the 

cymantrene- sC18-bioconjugates. The cellular internalization of these conjugates was studied with 

confocal fluorescence microscopy on MCF-7 cells. 

References 

1. K. Splith, I. Neundorf, W. Hu, H. W. Peindy N'Dongo, V. Vasylyeva, K. Merz, U. Schatzschneider, 

Dalton Trans. 2010, 39, 2536-2545. 

2. I. Neundorf, J. Hoyer, K. Splith, R. Rennert, H. W. Peindy N'dongo, U. Schatzschneider, Chem. 

Commun. 2008, 5604-5606.

P-14 


Coordination of a Peptide �-Turn Mimetic to Tungsten: 

Possible Applications for the Study of �-Sheets 

Adam N. Boynton a and Timothy P. Curran *a 

a Department of Chemistry, Trinity College, Hartford, CT 06106 USA 

Email: timothy.curran@trincoll.edu 

In 1995 Kemp and Li described the synthesis of 2-amino-2'-carboxyphenylacetylene (1) and its use as 

a peptide turn mimetic. 1,2 Their work showed that 1 does function as a �-turn mimetic, and that 

1 

peptide derivatives incorporating 1 adopted �-sheet structures. A key structural element in 1 is the 

alkyne group that links both phenyl rings. Because of our ongoing interest in the use of tungstenalkyne 

coordination for generating constrained peptides, 3,4,5 we have begun investigations into whether 

peptide derivatives of 1 can be reacted with W(CO)3(dmtc)2 to yield tungsten-bis(alkyne) complexes 

(like 2), and whether the peptides maintain a �-sheet structure after coordination to tungsten. If the 

peptides do maintain their sheet structure, then it would be of interest to know whether the two �sheets 

interact with each other via stacking arrangements. Owing to solubility and oligomerization 

issues, there are very few model systems for investigating �-sheet stacking interactions. 

2 

N 

H 

O 

O 

N 

H 

H 

N 

O 

O 

H 

N 

S 

S S 

W 

S 

O 

H 

N 

H 

N 

O 

72 

O 

N 

H 

O 

NH 2 

N 

H 

O 

OH 

S S 

= 

H3C S 

N 

H3C S 

This presentation will detail the status of our efforts to prepare and study these novel 

bioorganometallic species. 

References 

1. D. S. Kemp, Z. Q. Li, Tetrahedron Lett., 1995, 36, 4175-4178. 

2. D. S. Kemp, Z. Q. Li, Tetrahedron Lett., 1995, 36, 4179-4180. 

3. T. P. Curran, A. L. Grant, R. L. Lucht, J. C. Carter, J. Affonso, Org. Lett., 2002, 4, 2917-2920. 

4. T. P. Curran, R. S. H. Yoon, B. R. Volk, J. Organometallic Chem., 2004, 689, 4837-4847. 

5. T. P. Curran, A. B. Lesser, R. S. H. Yoon, J. Organometallic Chem., 2007, 692, 1243-1254.

P-15 


Synthesis and Characterisation of Palladium Bioconjugates 

Jan Dittrich a and Nils Metzler-Nolte* a 

a Ruhr-University Bochum, Faculty of Chemistry and Biochemistry, Department of 

Inorganic Chemistry I, Universitätsstr. 150, 44801 Bochum, Germany 

E-mail: Jan.Dittrich@rub.de 

Some transition metals like gold and platinum play a major role in anti-tumor research. 1,2 Palladium is 

a homologue element of platinum with related chemical behaviour, but is not in focus of cancer 

research until now. The ligand exchange rate of palladium is much higher than the one of platinum, 

consequently cispalladium would not work as an anticancer drug. The goal we are striving for are 

palladium bioconjugates like 1. A suitable metal complex is formed from a cyclometallated palladiumazide 

3 and methyl 2-isocyanoacetate, which undergo a [3+2] cycloaddition reaction to yield after 

rearrangement an ester functionalised palladium-tetrazole. After saponification this compound can be 

linked to an amino acid or peptide, both in solution and on solid phase. The compounds were 

characterized by multidimensional and multinuclear NMR techniques, mass spectrometry and IR 

spectroscopy. 

References 

N 

Pd 

N 

N 

N 

N N 

1 

O 

H 

N 

1. I. Ott, Coord. Chem. Rev. 2009, 52, 763-770. 

2. Z. Guo, P.J. Sadler, Angew. Chem. Int. Ed. Engl. 1999, 38, 1512-1531. 

3. Y.J. Kim, X. Chang, J.T. Han, M.S. Lim, S.W. Lee, Dalten Trans. 2004, 3699-3708. 

O 

N 

H 

73 

O 

OH 

H 

N 

O 

N 

H 

O 

H 

N 

O 

OH

P-16 


Conjugation of Rheniumtricarbonyl Bisimine Complexes to Polylactides - 

Fluorescent Polymers for in vivo Tumour Diagnostics 

Nadine E. Brückmann a and Peter C. Kunz* a 

a Heinrich-Heine-University of Düsseldorf, Department of Inorganic Chemistry I, 

Universitätsstr. 1, 40225, Düsseldorf, Germany. E-mail: peter.kunz@uni-duesseldorf.de 

In order to improve current cancer pharmaceuticals, new polymer-based transport systems are being 

developed that deliver the drug directly to the tumour, where it can subsequently be released. 

Macromolecules can accumulate in tumours due to the EPR-effect. 1 Although polymers are now 

widely used in therapeutic approaches, only a few examples of diagnostically applied polymerconjugates 

exist. 2 Rheniumtricarbonyl bisimines e.g. are useful as dyes for fluorescence microscopy. 

Their fluorescence emission lies in the visible light spectrum, resulting from a metal-to-ligand-chargetransfer 

(MLCT). These transitions typically have large Stokes shifts, which makes the fluorescence 

easily destinguishable from tissue autofluorescence. 3 Attachment of these rhenium cores to ligandfunctionalised 

polylactides leads to biodegradable fluorescent polymers. 

In particular, rheniumtricarbonyl complexes of 2,2’bipyridine (bipy), 1,10-phenanthroline (phen) as 

well as dipyrido[3,2-a:2’,3’-c]phenazine (dppz) were prepared. Absorption and emission data were 

ascertained, cytotoxicity was determined on A2780 ovarian cancer cell lines and the in vivo 

localisation was examined by confocal microscopy. Investigations into their degradation kinetics are 

currently ongoing. 

References 

1. H. Maeda, J. Wu, T. Sawa, Y. Matsamura, K. Hori, J. Cont. Rel. 2000, 65, 271-284. 

2. A. Mitra, A. Nan, H. Ghandehari et al., Pharm. Res. 2004, 21(7), 1153-1159. 

3. A. Amoroso, M. Coogan, J.E. Dunne et al., Chem. Commun. 2007, 29, 3066-3068. 

74

P-17 


Organometallic Complexes Coupled to Cell-Penetrating Peptides: Generation of 

Promising New Cytostatic Compounds 

K. Splith, a Jan Hoyer, a Wanning Hu, b Ulrich Schatzschneider, b Yvonne Geldmacher, c 

Malte Kokoschka, c William S. Sheldrick, c and Ines Neundorf *a 

a Leipzig University, Faculty of Biosciences, Pharmacy and Psychology, Department of Biochemistry, 

Brüderstr. 34, 04103, Leipzig, Germany. b Ruhr-University Bochum, Faculty of Chemistry and 

Biochemistry, Department of Inorganic Chemistry I, Universitätsstr.150, 44801, Bochum, Germany. 

c Ruhr-University Bochum, Faculty of Chemistry and Biochemistry, Department of Analytical 

Chemistry, Universitätsstr.150 ,44801, Bochum, Germany. E-mail: splith@uni-leipzig.de 

Bioorganometallic chemistry has become more and more important in several fields, especially in the 

development of new drugs for cancer treatment. A number of metal-based building blocks have 

promising features for applications in therapy and diagnosis. Introduction of a metal centre could add 

new features which might help to overcome some problems in cancer treatment. However the low 

water solubility and bioavailability of these organometallic compounds inhibits their therapeutic use in 

medicine. Recently, so called cell-penetrating peptides (CPP) have emerged as potent tools to 

introduce substances into cells. CPP are an inhomogenic group of peptides that share the ability to 

translocate in a large number of different cell-lines without the need of a receptor or transporter 

molecule. Thereby they are capable to transport various cargos inside cells, like proteins, 

oligonucleotides, nanoparticles or small organic drugs. 1,2 

This work describes the coupling of metal-based building blocks to cell-penetrating peptides based on 

an antimicrobial peptide cathelicidin CAP18. 3 Synthesis was achieved by solid phase peptide synthesis 

using standard Fmoc chemistry and activation by HOBt/DIC. Several different metal complexes have 

been investigated, e.g. half-sandwich-complexes of different metals. Cellular uptake of the new 

bioconjugates was investigated with different methods and high accumulation in different tumour cells 

could be observed. Furthermore, cell viability assays showed that those organometallic peptide 

conjugates are very potent and possess promising cytotoxic properties. 4,5,6 

References 

1. K. M. Stewart, K. L. Horton, S. O. Kelley, Org. Biomol. Chem. 2008, 6, 2242-2255. 

2. I. Neundorf, R. Rennert, J. Franke, I. Közle, R. Bergmann, Bioconjugate Chem. 2008, 8, 1596-603. 

3. I. Neundorf, R. Rennert, J. Hoyer, F. Schramm, K. Löbner, I. Kitanovic, S. Wölfl, Pharmaceuticals 2009, 2, 

49-65. 

4. I. Neundorf, J. Hoyer, K. Splith, R. Rennert, H.W. Peindy N’dongo, U. Schatzschneider, Chem. Commun. 

2008, 43, 5604-5606. 

5. K. Splith, I. Neundorf, W. Hu, H.W. Peindy N'dongo, V. Vasylyeva, K. Merz, U. Schatzschneider, Dalton 

Trans. 2010, 39, 2536-2545. 

6. K. Splith, W. Hu, U. Schatzschneider, R. Gust, I. Ott, I. Neundorf, manuscript submitted. 

75

P-18 


Interaction between [Ru(� 6 -p-cym)(H2O)3] 2+ and (O,O) Donor Ligands of 

Biological Importance in Aqueous Solution 

Péter Buglyó, *a Linda Bíró, a and Etelka Farkas a 

a University of Debrecen, Faculty of Science and Technology, Department of Inorganic and Analytical 

Chemistry, P. O. Box 21, H- 4032 Debrecen, Hungary. E-mail: buglyo@delfin.unideb.hu 

Numerous Ru(III) and Ru(II) complexes have been synthesized, characterized in the solid state and 

tested for antitumor activity. The most promising candidates are shown to act differently both in vitro 

and in vivo from the antitumor platinum complexes currently used in the therapy. Beside Ru(III) 

complexes with octahedral geometry half-sandwich organometallic Ru(II) complexes with typical 

“piano stool” geometry are also investigated intensively. 1 

Recently we have shown that one class of important biomolecules, monohydroxamates (being also 

(O,O) chelators), are capable to form stable complexes with the [Ru(� 6 -p-cym)(H2O)3] 2+ core both in 

the solid state and in aqueous solution. 2 We have also explored in detail the hydrolysis of the metal ion 

using different (pH-potentiometry, NMR, UV-VIS and ESI-MS) techniques and estimated the stability 

constants of the hydroxo complexes formed in the H + –[Ru(� 6 -p-cym)(H2O)3] 2+ system. Taking into 

consideration the hydrolysis we were able to obtain the pH dependent speciation of the H + –[Ru(� 6 -pcym)(H2O)3] 

2+ –meaha system (meaha = N-methyl-acetohydroxamate) and to determine the 

composition and stability constants of the complexes formed with the monohydroxamate. 

In order to compare the [Ru(� 6 -p-cym)(H2O)3] 2+ binding strength of meaha with that of other (O,O) 

donors partly used as building blocks in ruthenium complexes with potential anticancer activity or 

present in biofluids a systematic study has been carried out. Ligands capable to form five membered 

(oxalic acid, lactic acid, kojic acid, maltol, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one, 1,2dihydroxybenzene-3,5-disulfonate) 

and six-membered (cyclobutane-1,1-dicarboxylic acid, 

acetylacetone, salicylic acid) chelates in which the donor atoms exhibit different basicity were choosen 

and the interaction of these chelators with [Ru(� 6 -p-cym)(H2O)3] 2+ was investigated. This contribution 

summarises the results of a detailed solution equilibrium work. During this study our goal was to 

estimate the speciation and to compare the composition and stabiliy constants of Ru-(O,O) type 

complexes formed applying different (pH-potentiometry, 1 H-NMR, ESI-MS) experimental techniques. 

References 

1. (a) P. C. A. Bruijnincx, P. J. Sadler, Adv. Inorg. Chem., 2009, 61, 1-62. (b) W. Kandioller, C. G. 

Hartinger, A. A. Nazarov, M. L. Kuznetsov, R. O. John, C. Bartel, M. A. Jakupec, V. B. Arion, B. K. 

Keppler, Organometallics, 2009, 28, 4249-4251. 

2. P. Buglyó, E. Farkas, Dalton Trans., 2009, 8063-8070. 

Acknowledgement: We thank the members of the EU COST Action D39 for motivating discussions. 

This work was supported by the Hungarian Scientific Research Fund (OTKA K76142). 

76

P-19 


Organometallic Osmium Arene Complexes with Potent Cancer Cell Cytotoxicity 

Ying Fu, a Abraha Habtemariam, a Ana M. Pizarro, a Sabine H. van Rijt, a Guy J. Clarkson, a 

and Peter J. Sadler *a 

University of Warwick, Department of Chemistry, Gibbet Hill Road, Coventry, CV4 7AL, 

U.K, E-mail: fuyingpku@gmail.com 

Arene complexes of the heavier congener osmium(II) display similar 

structures in the solid state to those of Ru II but are subtly different 

with regard to their chemical reactivity. For example, Os II arene 

ethylenediamine chlorido complexes hydrolyze ca. 40x more slowly 

and the related aqua adducts have pKa values for Os�OH2/OH which 

are ca. 1.5 pKa units lower (more acidic) than those of the analogous 

Ru II complexes. 1,2 Faster ligand exchange in Os II complexes can be 

achieved by incorporating oxygen-containing chelating ligands, e.g. 

picolinates. 3,4 In general they show a different cytotoxicity profile and 

have a larger reactivity window compared to Ru arene complexes. 

The synthesis of a range of osmium complexes of the general 

structure shown will be discussed including the X-ray crystal 

structures of five complexes. Surprisingly, several of these Os II 

Arene 

X 

Os 

N 

N 

complexes with iodide as the X ligand are an order of magnitude [Os(Arene)(NN)X] 

more potent than the clinically-used drug cisplatin towards a range of human cancer cell lines. 

We thank Dr. Michael Khan (Biological Sciences) for provision of facilities for cell culture, and the 

MRC, EPSRC (Knowledge Transfer Network), ERC and EU EDRF/AWM (APOC) for funding, and 

members of COST Action D39 for discussion. 

+ 

References 

1. Peacock, A. F. A.; Habtemariam, A.; Fernandez, R.; Walland, V.; Fabbiani, F. P. A.; Parsons, S.; 

Aird, R. E.; Jodrell, D. I.; Sadler, P. J. J. Am. Chem. Soc. 2006, 128, 1739-1748. 

2. Wang, F.; Habtemariam, A.; van der Geer, E. P.; Fernandez, R.; Melchart, M.; Deeth, R. J.; Aird, 

R.; Guichard, S.; Fabbiani, F. P.; Lozano-Casal, P.; Oswald, I. D.; Jodrell, D. I.; Parsons, S.; Sadler, P. 

J. Proc Natl Acad. Sci.U.S.A. 2005, 102, 18269-18274. 

3. Peacock, A. F. A.; Sadler, P. J. Chem.--Asian J. 2008, 3, 1890-1899. 

4. van Rijt, S. H.; Peacock, A. F. A.; Johnstone, R. D. L.; Parsons, S.; Sadler, P. J. Inorg. Chem. 2009, 

48, 1753-1762. 

77

P-20 


Cytotoxic Apoptosis-Inducing Organometallic Rhodium Complexes with 

Substituted Polypyridyl Ligands 

Yvonne Geldmacher, a Riccardo Rubbiani, b Ingo Ott, b and William S. Sheldrick a* 

a Ruhr-Universität Bochum,Faculty of Chemistry and Biochemistry, Department of Analytical 

chemistry, Universitätsstr. 150, 44780 Bochum, Germany, b Technical University of Braunschweig, 

Department of Pharmaceutical Chemistry, Beethovenstr. 55, 38106 Braunschweig, Germany 

E-mail: yvonne.geldmacher@rub.de 

The complexes of the type [(η 5 -C5Me5)RhCl(pp)]CF3SO3 (with pp= dpq, dppz, dppn) represent a new 

class of cytotoxic substances. Cytotoxicity and cellular uptake studies on the HEK-293, MCF-7 and 

HT-29 cell lines have been employed to establish relationships between the structure and the activity 

of the complexes. UV/Vis kinetic, thermal denaturation and CD studies have shown, that the prefered 

binding mode of the complexes to DNA is intercalation. [(η 5 -C5Me5)RhCl(dppz)]CF3SO3 invokes the 

largest increase in Tm with a value 12 °C being recorded for a 1:10 complex/DNA mixture in the 

denaturation experiment. In contrast, complexes containing the smaller chelate ligands with pp = en, 

bpy and phen exhibit negative ΔTm values, which indicates the presence of a covalent binding mode. 

CD spectra for the complex/DNA mixtures with pp = dpq and dppz contain a negative ICD-signal in 

the range 280-300 nm, which also indicates intercalation. Viscosity measurements also confirm the 

conclusions from UV/Vis and CD studies. 1 

100 

Figure 1: crystal structure of Figure 2: DNA-fragmentation after a 72 h treatment of 

[(η 5 -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 BJAB cells with [(η 5 -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 at different 

concentrations 

The biological activity also correlates with the lipophilicity and thereby with the size of the 

polypyridyl ligand. The IC50 values decrease in the series en, bpy>> phen,dpq > dppz > dppn. One 

goal of our ongoing studies is to improve the cell selectivity and identify lead substances by varying 

the ligands L and pp in complexes [(η 5 -C5Me5)RhL(pp)](CF3SO3)n. It has previously been shown that 

there are significant differences between the cytotoxicities of Pt(II) complexes with methylated 1,10phenanthroline 

ligands. 2 We now report studies of the biological activity of [(η 5 - 

C5Me5)RhCl(pp)]CF3SO3 complexes containing methylated phenanthroline ligands and other 

substituted polypyridyl ligands. Measurements of the LDH release for lymphoma (BJAB) cells after 

1h incubation with phen, 5,6-Me2phen and dppz complexes demonstrated that unspecific necrosis is 

negligible. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72 

h (Figure 2). 

References 

apoptotic cells [%] 

75 

50 

25 

0 

1. M.A. Scharwitz, I. Ott, Y. Geldmacher, R. Gust, W.S. Sheldrick, J. Organomet. Chem. 2008, 693, 

2299-2309. 

2. C.R. Brodie, J.G. Jollins, J.R. Aldrich-Wright, Dalton Trans. 2004, 1145. 

78 

Co DMSO0.1 1 5 10 25 50 75 100 

concentration [µM]

P-21 


Antiproliferative Activity of Cationic and Neutral Heterobimetallic 

Ferrocene-(Vinyl)Ru(CO)Cl(P i Pr3)2 Complexes 

Konrad Kowalski, *a Ingo Ott, *b Rainer. F. Winter, c and Ronald Gust d 

a University of Łódź, Faculty of Chemistry, Department of Organic Chemistry, Tamka 12, 91-403 

Łódź, Poland. b Technische Universität Braunschweig, Institute of Pharmaceutical Chemistry, 

Beethovenstraße 55, 38106 Braunschweig, Germany. c Universität der Regensburg, Institut für 

Anorganische Chemie, Universitätsstraße 31, D-93040 Regensburg, Germany. d Freie Universität 

Berlin, Institute of Pharmacy, Königin-Luise-Str. 2+4, 14195 Berlin, Germany. 

E-mail: kondor15@wp.pl 

Recently, some of us reported 1 on the mixed ferrocene ruthenium organometallic species 1 and 2 with 

the main focus on measuring the degree of electron delocalization in mixed-valent 2 and its medium 

dependence. In the bioorganometallic chemistry field the cytotoxic activity of some ferrocenium salts 

and the lack of activity of the corresponding ferrocenes is well known 2 . On the other hand the 

anticancer activity of mixed ferrocene/ruthenium complexes has been recently reported 3 . Considering 

these data, complexes 1 and 2 along with their monometallic counterparts 3-8 have been subjected 

toward biological studies 4 . Antiproliferative activity of 1-8 was carried out in HT-29 colon carcinoma 

and MCF-7 breast cancer cells. Both bimetallic derivatives 1 and 2 exhibited IC50 values between 4.8 

μM and 16.8 μM. These values are within the range of common cytostatics such as cisplatin and 5fluorouracil 

investigated as control in the same assay. In addition our tests show higher 

antiproliferative activity of cationic 2 than of neutral 1. In order to rationalize this observation the 

cellular uptake of 1, 2 and 4 was determined by measurement of the ruthenium content of cells 

exposed to the complexes by atomic absorption spectroscopy. Unexpectedly, the cellular uptake of 

cationic 2 exceeded those of neutral 1 and were comparable to those exhibited by 4. This results 

suggest that 2 might be effectively transported across cellular lipid membranes by an active transporter 

system. Such a transporter systems are known to be crucial factors for cellular metal biodistribution. 

However, they haven’t been identified for any cationic ferrocenes yet. 

Fe 

P i Pr 3 

Ru 

P i Pr 3 

Cl 

CO 

Fe 

PiPr + 

3 

Ru 

P i Pr 3 

Cl 

CO 

PF 6 - 

1 2 3 

79 

Fe 

R 

R = -OCH 3 

-F 

-CF 3 

-N(CH 3) 2 

-CHO 

Acknowledgements: KK is grateful to the Alexander von Humboldt-Stiftung for a research 

fellowship at the group of Prof. Dr. R. F. Winter, University of Regensburg 

References 

1. K. Kowalski, M. Linseis, R. F. Winter, M. Zabel, S. Záliš, H. Kelm,; H-J. Krüger, B. Sarkar, W. 

Kaim, Organometallics 2009, 28, 4196. 

2. G. Tabbi, G. Cassino, G. Cavigiolio, D. Colangelo, A. Ghiglia, I Viano, D. Osella, J. Med. Chem. 

2002, 45, 5786. 

3. M. Auzias, B. Therrien, G. Süss-Fink, P. Stepnicka, W.H. Ang, P. J. Dyson, Inorg. Chem. 2008, 47, 

578. 

4. I. Ott, K. Kowalski, R. Gust, J. Maurer, P. Mücke, R.F. Winter, Bioorg. Med. Chem. Lett. 2010, 20, 

866-869. 

P i Pr 3 

Ru 

P i Pr 3 

4 

5 

6 

7 

8 

Cl 

CO

P-22 


Green Chemistry in the Production of Ferrocene Derivatives Using Recyclable 

Solid Heteropolyacids as Catalysis 

Jorge Jios, a Gustavo Romanelli, b and Nils Metzler-Nolte *c 

a Laseisic (CIC-CONICET-UNLP), Departamento de Química, Facultad de Ciencias Exactas, UNLP. 

Camino Centenario e/505 y 508, CP1897, Gonnet, Argentina. b Centro de Investigación y Desarrollo 

en Ciencias Aplicadas “Dr. J. J. Ronco” (CINDECA), Departamento de Química, Facultad de 

Ciencias Exactas, UNLP-CONICET. Calle 47 Nº 257, B1900AJK La Plata, Argentina. c Lehrstuhl für 

Anorganische Chemie I, Bioanorganische Chemie, Fakultät für Chemie und Biochemie, Ruhr- 

Universität Bochum, Universitätsstrasse150, D-44801 Bochum, Germany. E-mail: 

jljios@quimica.unlp.edu.ar 

Dihydropyrimidinone are known to exhibit a wide range of biological activities such as antiviral, 

antitumour, antibacterial, and anti-inflammatory properties. 1 Several reagents/methods have been 

reported for their preparation under milder and more efficient procedures such as Amberlyst-15, 

Nafion-H, KSF clay with dry acetic acid under microwave irradiation, ionic liquids, cerric ammonium 

nitrate under ultrasonication, Lewis acids with transition metals, lanthanides, and indium chloride. 2 In 

this work we present an improved procedure for the obtention of dihydropyrimidinones bearing 

ferrocene in a three component one-pot condensation reaction using heteropolyacid catalysts (Figure 

1). 

R 

Fe +2 

+ 

O O 

C 

O 

H 

R´ 

NH 2CONH 2 

Superacid Catalyst 

The results are discussed in terms of the catalyst used, their selectivity and the reaction conversion 

degree. The aim of this work is investigate a convenient synthesis for the production of new 

metallocene carrying heterocyclic compounds with biological activities. The spectral data are 

discussed in detail. 

References 

1. C. O. Kappe, Tetrahedron 1993, 49, 6937-6963, and references cited therein. 

2. (a) F. Bigi, S. Carloni, B. Frullanti, R. Maggi, G. Sartori, Tetrahedron Lett. 1999, 40, 3465-3468. 

(b) J. Peng, Y. Deng, Tetrahedron Lett. 2001, 42, 5917-5919. (c) J. S. Yadav, B. V. S. Reddy, K. B. 

Reddy, K. S. Raj, A. R. J. Prasad, Chem. Soc. Perkin Trans. 1 2001, 1939-1941. (d) E. H. Hu, D. R. 

Sidler, U. H. Dolling, J. Org. Chem. 1998, 63, 3454-3457. (e) Y. Ma, C. Qian, L. Wang, M. Yang, J. 

Org. Chem. 2000, 65, 3864-3868. (f) J. Lu, Y. Bai, Z. Wang, B. Yang, H. Ma, Tetrahedron Lett. 2000, 

41, 9075-9078. (g) B. C. Rannu, A. Hajra, U. Jana, J. Org. Chem. 2000, 65, 6270-6272. (h) H. N. 

Karade, M. Sathe, M. P. Kaushik. Molecules 2007, 12, 1341-1351. 

80 

R' 

O 

R 

Fe +2 

N 

H 

NH 

O

P-23 


Antiproliferative Activity of Diphenylmethylidenyl-[3]ferrocenophanes on Breast 

and Prostate Hormone-independent Cancer Cell Lines 

Meral Gormen, a Pascal Pigeon, a Siden Top,* a Elizabeth A. Hillard, a Marie-Aude Plamont, a 

Anne Vessières, a amd Gérard Jaouen a 

a ENSCP, Laboratoire Charles Friedel, UMR 7223, 11, Rue Pierre et Marie Curie, 75231, Paris, 

Cedex 05, France. E-mail: meral-gormen@chimie-paristech.fr 

Breast cancer is the leading cause of cancer death among women in the Western world and accounts for 

23% of all female cancer cases worldwide. 1 In terms of incidence rate, breast cancer touches one woman in 

eight in Western countries. 

Tamoxifen, whose active metabolite is hydroxytamoxifen (1), is currently the most widely used antiestrogen 

in the adjuvant therapy of hormone-dependent breast cancers. 2 However, it is known that one-third of these 

cases are hormone-independent cancers, and don’t respond to tamoxifen therapy. We found that 

hydroxyferrocifen (2) and ferrocifenol (3) exhibit strong antiproliferative activities against both hormonedependent 

MCF-7 cancer cells and hormone-independent MDA-MB-231cancer cells. 3 

OH 

OH 

Fe 

Fe 

Fe 

O(CH2) 2N(CH3) 2 

OR 

1 2. R = (CH2) 3N(CH3) 2 

3. R = H 

4 5 

R1,R2= H,OH,NH2,NHAc It has recently been shown that dihydroxy [3]ferrocenophane 4 is 7 times more potent than ferrocifenol 3 on 

MDA-MB-231 cells. 4 We now extend our work on this new and interesting series by synthesizing other 

compounds by varying the nature of the substituents R1 and R2 (5). 5 These new compounds show high 

activity compared to that of classical ferrocene analogues. The inhibitory concentrations (IC50) of 5 on 

MDA-MB-231 cells range from 50 to 90 nM. 

Our work was extended to prostate cancer which is one of the most frequently diagnosed cancers and is the 

second leading cause of cancer death in men after lung. We found that [3]ferrocenophane derivatives are also 

active against PC3 hormone-independent prostate cancer cells with IC50 ranging from 20 to 140 nM. 

Synthesis and antitumor activities of [3]ferrocenophane derivatives will be presented. 

References 

1. (a) J. Ferley, F. Bray, P. Pisani, D. M. Parkin. GLOBOCAN 2002: Cancer Incidence, Mortality and 

Prevalence Worldwide. IARC CancerBase No. 5 version 20. IARCPress, Lyon, France, 2004. (b) A. 

Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, M. J. Thun, CA Cancer J Clin 2007, 57, 43-66. (c) R. Y. 

Wood, N.R. Della-Monica. Int. J. Older People Nursing, 2006, 1 (2), 75-84. 

2. (a) V. C. Jordan, J. Med. Chem., 2003, 46 (6), 883-908 (b) V. C. Jordan, J. Med. Chem., 2003, 46 (7), 

1081-1111. 

3. S. Top, A. Vessières, G. Leclercq, J. Quivy, J. Tang, J. Vaissermann, M. Huche, G. Jaouen. 

Chem. Eur. J., 2003, 9, 5223-5236. (b) A. Vessières, S. Top, P. Pigeon, E. Hillard, L. Boubeker, 

D. Spera, G. Jaouen J. Med. Chem., 2005, 48, 3937-3940 

4. D. Plazuk, A. Vessieres, E.A. Hillard, et al. J. Med. Chem., 2009, 52, 4964-4967. 

5. M. Gormen, P. Pigeon, E.A. Hillard, et al. Tetrahedron Lett., 2010, 51, 118-120. 

81 

HO 

OH 

R 1 

R 2

P-24 


Cell Uptake and Cytotoxicity of Metal-Peptide-Bioconjugates 

Annika Groß a and Nils Metzler-Nolte* a 



E-mail: Annika.Gross@rub.de 

Organometallic conjugates of cell-invasive peptides are proposed as interesting candidates for a future 

generation of novel cancer therapies since they are structurally unique compared to other classes of 

routinely used cytotoxic drugs. We therefore aimed to synthesise various metal compounds linked to 

peptides. 

Solid and solution phase methods were used to generate peptides and their fluorescent and metal 

containing analogs. Cell uptake, and the effect of the metal was investigated by comparison of 

metallocene-peptide conjugates to acetylated peptides using fluorescence microscopy. Intracellular fate 

was examined in co-localisation studies using compartment-specific dyes. 

Cytotoxicity studies of functionalised peptides were performed using the Resazurin and Crystal Violet 

proliferation assays on different cell lines. 

Peptides containing acetyl, ferrocene, ruthenocene, cobaltocene and cobalt carbonyl moieties were 

successfully synthesised, purified and characterised. All bioconjugates were cell permeable and colocalised 

with a lysosome-specific dye. Metallocene and reference compounds were not toxic in the range 

100-1000 µM. However, depending on the cell line, the cobalt carbonyl gave IC50 values down to 10 µM 

in these assays. Ferrocene, ruthenocene and cobaltocenium show no cytotoxicity, but cobalt carbonyl 

renders the conjugate cytotoxic. 

82

P-25 

R 

OH 

O 

N 

R = Ph : hydroxytamoxifen 

R = Fc : hydroxyferrocifen 


On the Mechanism of Hydroxyferrocifen Cytotoxicity 

Didier Hamels, a Patrick M. Dansette, b Elizabeth A. Hillard, a Siden Top, a Anne Vessières, a Gérard 

Jaouen, a and Daniel Mansuy. b 

a Chimie ParisTech, Laboratoire Charles Friedel, UMR 7223; 11, rue Pierre et Marie Curie 

75231 Paris Cedex 05, France. b Université Paris Descartes, Laboratoire de Chimie et Biochimie 

Pharmacologiques et Toxicologiques, UMR 8601; 45, rue des Saints Pères 75006 Paris, France. 

E-mail : didier-hamels@chimie-paristech.fr 

Breast cancer is one of the most common cancers of women in the Western World. When the estrogen 

receptor (ER) is expressed in tumor cells, the breast cancer is categorized as hormone-dependent 

(ER+). ER+ breast cancer is the most commonly diagnosed (2 out of 3 cases), and can be treated with 

the help of selective estrogen receptor modulators (SERMs). Some SERMs act as ER antagonists in 

the cancer cell, thus preventing cell division. Unfortunately, SERMs are not active against ER� breast 

cancer cells, and alternative molecules have to be found. 

Fe 

Me 

O 

Me 

A hydroxyferrocifen 

derivative QM (QM-1) 

In 1996, Jaouen et al. designed and synthesized “hydroxyferrocifen”, 

a compound in which one of the phenyl groups of 

hydroxytamoxifen had been replaced by a ferrocene moiety. 1 

The original idea was to combine the antiestrogenic effect of 

hydroxytamoxifen with the potentially cytotoxic effect of 

ferrocene. Our expectations were rewarded by the discovery 

that hydroxyferrocifen is indeed active against ER+ (MCF-7) 

and ER� (MDA-MB-231) breast cancer cells. 2 When the side 

chain was extended to three carbon atoms, the resulting Fc-OHTam[3] molecule was found to be even 

more cytotoxic. 

We thus decided to investigate the mechanism of action of the 

hydroxyferrocifens and related molecules. We hypothesized that 

their cytotoxicity is due to the in situ formation of highly 

cytotoxic quinone methide (QM) species. This interpretation was 

supported by electrochemical experiments 3 but neither 

hydroxytamoxifen 4 nor hydroxyferrocifen QMs had ever been 

isolated this far. Metabolic and chemical oxidation of Fc- 

OHTam[3] and three related conjugated ferrocene phenols 

allowed us to isolate and characterize the QMs by 1 H and 13 C 

NMR spectroscopy, and by X-ray crystallography in one case. 

The obtained QMs were then tested against ER� breast cancer 

cells (MDA-MB231) and were found to be cytotoxic. 5 This strongly supports the hypothesis that QMs 

are indeed relevant intermediates in the cytotoxicity of hydroxyferrocifens and related molecules 

against breast cancer cells. We are currently investigating the reactivity of such QMs in order to identify 

potential biological targets. 

References 

1. Top et al., Chem. Com. 1996, 955-956. 

2. Top et al., Chem. Eur. J. 2003, 9, 5223-5236. 

3. Hillard et al., Angew. Chem. Int. Ed. 2006, 45, 285-290. 

4. Fan et al., Chem. Res. Toxicol. 2000, 13 (1), 45-52. 

5. Hamels et al., Angew. Chem. Int. Ed. 2009, 48, 9124-9126. 

83 

QM-1 X-ray crystal structure

P-26 


Influence of Cisplatin and Other (Bio-)organometalic Compounds on Changes in 

Cellular Signaling Using Novel Phosphoprotein Microarray Elisa Assays 

Pavlo Holenya, a Igor Kitanovic, a and Stefan Wölfl *a 

Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Germany 

Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany 

E-mail: wolfl@uni-hd.de 

Understanding aspects of the regulatory network of signaling pathways and their role in the 

development of the diseases is one of the crucial starting points in drug research. Signal transduction 

in cells is regulated, among other things, by phosphorylation and dephosphorylation of numerous 

signaling proteins. In many cases, phosphorylation reflects the activation state of those proteins within 

pathways that control various biological responses. In order to understand how drugs influence cells 

by modulating different pathways, it is highly desirable to simultaneously measure the 

phosphorylation states of diverse signaling proteins and temporarily monitore their levels in cells. 

For this we used a novel technology based on protein microarray platforms ArrayTube TM and 

ArrayStrip TM developed by CLONDIAG Chip Technologies, Jena. Both platforms represent less 

expensive and easy to handle systems for the development of protein arrays. The heart of the device is 

a chemically modified glass surface assembled to form the bottom of a 1.5 ml plastic polystyrol 

microtube or a standard well of a 96-well plate. Capture antibodies are deposited onto agarose-film 

coated glass surface by contact spotting. Handling of the protein chip is easy and rapid and involves 

the simple steps of an ELISA in a sandwich format. Specific interactions of antibody and antigen are 

simply revealed by colorimetric detection. Acquisition and analysis of processed chip images are 

performed by optical transmission microscopy in combination with image analysis software. 

Using the ArrayTube TM and ArrayStrip TM platforms and commercially available capture and detection 

antibodies, we established a protocol to quantitatively analyze changes in protein phosphorylation 

upon treatment with diverse organometallic compounds. We demonstrate high sensitivity and 

specificity of the microarrays and show quantitative analysis of several phosphorylated proteins, 

among them phospho GSK-3β, phospho RSK1, phospho Akt1, phospho p38α, phospho Erk1, phospho 

Erk2, phospho CREB, phospho TOR, phospho Src, phospho JNK, phospho p53, phospho STAT3, 

phospho ATM. 

Our results show that these newly developed arrays enable reliable evaluation of multiple target 

protein phosphorylation in a single sample. The method requires minimal sample volumes (~10 μl) 

and minimal amount of total protein (~1 μg) to obtain quantitative data, and it enables rapid evaluation 

of multiple analytes. 

We thank Clondiag GmbH, Jena, Germany for providing the microarray technology and the 

colleagues from the DFG-Forschergruppe FOR630 for bioorganometallic substances. 

84

P-27 


Variable Binding of Heterodinuclear (Cu, Fe) Organometallics to N and O Donor 

Functions of Guanine, Pterin, Lumazine and Alloxazine Heterocycles 

Rajkumar Jana, a Biprajit Sarkar, a Jan Fiedler, b and Wolfgang Kaim *a 

a Institut für Anorganische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70550, Stuttgart, 

Germany; b J. Heyrovský Institute of Physical Chemistry, v.v.i., Academy of Sciences of the Czech 

Republic, Dolejškova 3, 182 23 Prague 8, Czech Republic. E-mail: jana@iac.uni-stuttgart.de 

Co-ordination compounds of the first row transition elements with small biorelevant heterocycles such 

as coenzymes, vitamins, and also nucleobases are frequently labile, precluding the isolation and 

structural identification of species present in solution equilibria. In contrast, complexes of the heavier 

d block elements are often inert as exemplified by the platinum and platinum metal coordination 

chemistry of nucleobases 1 and coenzymes 2 . Herein we wish to report a number of first row transition 

metal compounds which owe their stability to the use of a particular kind of organometallic complex 

fragments, viz., [(dopf)Cu] + , dopf = 1,1`-bis(diorganylphosphino)ferrocene. 

Bu t OC 

H 

N 

H 

The dopf ligands are being extensively used as scaffolding chelate ligands in catalysis 3, 4 , sometimes 

using their propensity for reversible one-electron oxidation at the ferrocene iron site. Our experience 

especially with the dppf ligand (dppf = 1,1`-bis(diphenylphosphino)ferrocene) in heterobimetallic 

[(dppf)Cu] + to stabilize complexes with unreduced strong acceptors such as α-azoimines 5 or oquinones 

6 has prompted us to explore the coordination of [(dppf)Cu] + and [(dippf)Cu] + , dippf = 1,1`bis(diisopropylphosphino)ferrocene, 

with other small biorelevant unsaturated molecules containing the 

lumazine, isoalloxazine, pterin and guanine heterocyclic structures. Synthesis and structural 

characterization will be reported as will be electrochemical studies on oxidation (ferrocene) and 

reduction (heterocycles). 

References 

N 

O 

N 

Fe 

R2P + PR2 Cu 

N 

N 

Me 

Bu t OC 

H 

N 

H 

N 

Fe 

R2P + PR2 Cu 

O 

N 

N 

N 

1. (a) D. Montagner, E. Zangrando, B. Longato, Inorg. Chem. 2008, 47, 2688-2695. (b) 

Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug; B. Lippert, Ed.; Wiley-VCH, 

Weinheim, 1999. 

2. Bioorganometallics: Biomolecules, Labelling, Medicine; G. Jaouen, Ed.; Wiley-VCH, Weinheim, 

2006. 

3. L. M. Alcazar-Roman, J. F. Hartwig, A. L. Rheingold, L. M. Liable-Sands, I. A. Guzei, J. Am. 

Chem. Soc. 2000, 122, 4618-4630. 

4. M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 8232-8245. 

5. S. Roy, M. Sieger, B. Sarkar, B. Schwederski, F. Lissner, T. Schleid, J. Fiedler, W. Kaim, Angew. 

Chem. Int. Ed. 2008, 47, 6192-6194. 

6. S. Roy, B. Sarkar, D. Bubrin, M. Niemeyer, S. Zalis, G. K. Lahiri, W. Kaim, J. Am. Chem. Soc. 

2008, 130, 15230-15231. 

85 

Me 

N 

O 

Fe 

R2P + PR2 O 

Cu 

N 

N N 

Me 

Me 

N 

O 

Fe 

R2P + PR 

O 

Cu 2 

N 

N N 

Me 

Me 

Me

P-28 


Synthesis, Structure and Anticancer Activity of new Complexes of Copper 

with Pyridoxal-semicarbazone 

Violeta Jevtovic, *a Dragoslav Vidovic, b Radmila Kovacecic, c and Sonja Kaisarevic c 

a University of Novi Sad, Faculty of Sciences, Department of Chemistry, D. Obradovica 3, 38121, 

Novi Sad, Serbia 

b University of Oxford, Chemical Research Laboratory,Masfield Road ,OX1 3TA, City, UK. 

c University of Novi Sad, Faculty of Sciences, Department of Biology, D. Obradovica 3, 38121, Novi 

Sad, Serbia. E mail: violeta.jevtovic@dh.uns.ac.rs 

With reaction of ligand pyridoxal-semicarbazone PLSC . 2H2O 1 and appropriate chloride, sulphate 

and thiocyanate salts Cu(II) in alcohol and water mixtures which were given in three new copper(II) 

complexes: [Cu(PLSC)Cl2](1),[Cu(PLSC)(H2O)(SO4)]2 . 3H2O(2), [Cu(PLSC)2(NCS)2](NCS)2 (3) 

(see Fig.1). Cytototoxic activity was evaluated by colorimetric sulforhodamine B (SRB) assay, after 

exposure of cells to tested compounds for 24 h and 72 h. (see Fig 2.) shows effect of different 

concentrations of tested compounds on two cell lines after 24 h and 72 h incubation times. The results 

suggest that compound (A) exibit no antiproliferative effect. Compound (B) exibit cytotoxic effects 

on both cell lines only after 72h treatment by the highest tested concentrations. Similar cytotoxicity 

patern was observed for compound (C) with aditional cytotoxic effect on MDA-MB-231 after 24 h 

treatment with the highest concentration. 

(1) (2) (3) 

Figure 1. The molecular structure of complexes 

Figure 2. Effects of compounds (1), (2) and (3) on cell proliferation of MCF7 and MDA-MB-231 

References 

1. V. Leovac, V.S. Jevtovic, Lj. Jovanovic, G.A. Bogdanovic, J. Serb. Chem. Soc. 2005, 70, 393-422. 

86

P-29 




Igor Kitanovic, a Ana Kitanovic, a Hamed Alborzinia, a Suzan Can, a Pavlo Holenya, a Elke Lederer, a 

Hans-Günther Schmalz, b Annegret Hille, c Ronald Gust, c Ingo Ott, d Aram Prokop, e Melanie Oleszak, f 

Yvonne Geldmacher, f William S. Sheldrick, f Gilles Gasser, g Nils Metzler-Nolte, h and Stefan Wölfl* a 

a Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Germany, b Institute of 

Inorganic Chemistry, University of Cologne, Germany, c Institute of Pharmacy, Department of 

Pharmaceutical Chemistry, Freie Universität Berlin, Germany, d Institute of Pharmaceutical 

Chemistry, Technische Universität Braunschweig, Germany, e Cologne City Hospital, Department of 

Oncology, Cologne, Germany, f Faculty of Chemistry and Biochemistry, Department of Analytical 

Chemistry, University Bochum, g Institute of Inorganic Chemistry, University of Zurich, h Faculty of 

Chemistry and Biochemistry, Department of Bioinorganic Chemistry, University of Bochum 

email: Igor.Kitanovic@urz.uni-heidelberg.de, wolfl@uni-hd.de 

In the past several decades metal compounds containing platinum became an essential part of many 

clinical protocols for anti-cancer therapy. Considered to be relatively unspecific compounds that block 

DNA-replication and cell cycle progression, metal-containing compounds were not in the research 

focus of medicinal chemistry. New developments in the chemistry of (bio-)organometallic compounds 

however lead to the discovery of several unexpected highly specific activities of new organometallic 

compounds and opened new important perspectives in this field. 

For cancer therapy cancer cell specific toxicity and apoptosis induction are highly desirable features of 

new potential drugs. Within our collaborative network a wide range of new (bio-)orgamometallic 

compounds were developed that show very distinct cytotoxic properties suggesting that rather than 

acting through a common mechanism different cellular targets are responsible for cytotoxicity and cell 

death induction. 

We will present a comprehensive analysis of the cellular response of human colorectal 

adenocarcinoma cells HT29 with very diverse organometallic compounds: ranging from FeIIsalophenes, 

through more classical bioorganometallic compounds to bioorganometallic compounds 

derived from established (non-metal containing) drugs. To elucidate their specific activity profile, 

standard cell based assays were combined with genome wide gene expression profiling using 

affymetrix gene expression arrays. Although the substances represent a wide range of different 

structures and metal cores, they all are highly cytotoxic and clearly induce apoptosis in HT-29 cells. 

For gene expression profiling concentrations just below the IC50 (cytotoxicity) were chosen to obtain 

more compound specific alterations in gene expression rather then common cytotoxicity profiles, in 

addition mRNAs were collected at different time points critical in the cellular response upon 

treatment. 

The results obtained show similar response characteristics, but also very compound specific changes. 

This clearly indicates very distinct biological properties and suggests common response mechanisms 

as well as high selectivity and target specificity. 

List of compounds: Hi41, CoASS (AG Gust), MH1 (AG Scheldrick), MeN69 (AG Schmaltz), 

FcOHTAM3, ReGG1 (AG Metzler-Nolte) 


87

P-30 


Organoiridium(III) and -rhodium(III) Bis-Intercalators: Influence of the 

Bridging Ligand on Cytotoxicity 

Malte Kokoschka, a Andreas Meyer, b Ingo Ott, b and William S. Sheldrick *a 

a Ruhr-Universität Bochum, Faculty of Chemistry and Biochemistry , Department of Analytical 

Chemistry, Universitätsstraße 150, 44801, Bochum, Germany. b Technische Universität 

Braunschweig, Institute of Pharmaceutical Chemistry, Beethovenstraße 55, 38106, Braunschweig, 

Germany. E-mail: malte.kokoschka@rub.de 

As we have recently shown, dinuclear iridium(III) polypyridyl complexes bridged by flexible ligands 

are capable of sequence selective intercalation into a synthetic DNA oligomer. 1 Induced structural 

changes in DNA – which have been proposed to account for the cytotoxicity of cisdiamminedichloroplatinum(II) 

– should be closely related to the molecular shape of the employed 

bridging ligand. Taking advantage of our findings from NMR assisted structure calculations on a 

double-stranded decanucleotide bis-intercalator adduct, we have started a systematic investigation of 

bis-intercalative compounds incorporating bridging ligands such as 1,3-benzenedithiol, 1,3- and 1,4benzenedimethanethiol 

with the ability to induce stronger distorsions into DNA. The resulting 

compounds have being studied with respect to their cytotoxicity and DNA interaction, respectively. 

[{(η 5 -C5Me5)Ir(dppz)}2(µ-2,9-dithiadecane)] 4+ bis-intercalated into the double-stranded decanucleotide 

d(5’-GCGCATCGGC-3’) as determined by NOESY NMR spectroscopy 

References 

1. M. Kokoschka, J.-A. Bangert, R. Stoll, W. S. Sheldrick, Eur. J. Inorg. Chem. 2010, 1507-1515. 

88

P-31 


Synthesis, Structures, Characterization and Biological Activities of Some 

Diorganotin(IV) Complexes 

See Mun Lee, *a H. Mohd. Ali, a and K. M. Lo a 

a University of Malaya, Faculty of Science, Department of Chemistry, 50603 Kuala Lumpur,Malaysia. 

E-mail: smlee@um.edu.my 

Metal complexes are widely prepared and have been successfully used in the treatment of numerous 

human diseases including cancer. Organotin(IV) complexes have been widely studied for their 

biological activities such as anticancer, antihistamine, antifungal and many others. Schiff base derived 

from substituted salicylaldehyde has been widely used as polydentate ligands in the preparation of 

metal complexes. In our present studies, a series of Schiff base ligands were prepared by reacting 3hydroxy-2-naphthoic 

hydrazide with substituted 2-hydroxyacetophenone. The diorganotin complexes 

were subsequently prepared by adding the ligands with diorganotin dichloride or oxide in 1:1 molar 

ratio and were characterized by various spectroscopic methods including IR, NMR spectroscopies. 

The X-ray structures of some of the diorganotin complexes namely 

{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV) 

{[1-(5-Bromo-2 oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dibutyltin(IV) 

{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dimethyltin(IV) and 

{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dimethyltin(IV) 

have been determined using single crystal X-ray diffractometry. The in vitro cytotoxic activity of the 

Schiff base ligands and diorganotin complexes has been evaluated against several cancer cell-lines 

such as HT-29, SKOV-3 and MCF7. 

References 

1. M. Gielen, Coord. Chem. Rev. 1996, 151, 41-51. 

2. A. J. Crowe, P. J. Smith, C. J. Cardin, H. E. Parge, F. E. Smith. Cancer Lett. 1984, 24 45-48. 

89

P-32 


Organometallic Iridium Anticancer Complexes 

Zhe Liu, Abraha Habtemariam, Ana Pizarri, Sally Fletcher, Guy Clarkson and Peter J. Sadler 

Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K. 

E-mail: Z.Liu.2@warwick.ac.uk 

Cisplatin has been used to treat various types of cancers for over 30 years, however, a number of 

serious side-effects of cisplatin have stimulated the long quest for other metal-based anticancer agents, 

especially drugs which possess a wider range of anticancer activity and with fewer side effects than 

cisplatin. There is much current interest in the design of ruthenium 1 and osmium 2 complexes as 

anticancer agents, but only a small amount of work has been done to investigate the antitumour 

activity of iridium complexes. 3 

Here we report the synthesis and characterization of a wide range of Ir(III) cyclopentadienyl 

complexes. We have studied their solid state structures, hydrolysis rates, reactivity towards 

nucleobases and acidity of aqua complexes. Their cell uptake and distribution and toxicity towards 

cancer cells have been studied and correlated with their chemical properties. Both the chemical and 

biological activity of these complexes show a strong dependence on the nature of the substituents on 

the cyclopentadienyl and the other ligands in the complexes. 

Acknowledgements: We thank WPRS (scholarship for Z.L), ERC (award for P.J.S.), EDRF and 

AWM for Science City funding, and members of COST Action D39 for stimulating discussions. 

References 

1. (a) A. Habtemariam, M. Melchart, R. Fernndez, S. Parsons, I. D. H. Oswald, A. Parkin, F. P. A. 

Fabbiani, J. E. Davidson, A. Dawson, R. E. Aird, D. I. Jodrell, P. J. Sadler, J. Med. Chem., 2006, 49, 

6858-6868. (b) J. M. Redemaker-Lakhai, D. van den. Bongard, D. Pluim, J. H. Beijnen, J. H. M. 

Schellens, Clin. Cancer Res. 2004, 10, 3717–3727. (c) I. Bratsos, S. Jedner, T. Gianferrara, E. Alessio, 

Chimia 2007, 61, 692-697. 

2. (a) A. F. A. Peacock, S. Parsons, P. J. Sadler, J. Am. Chem. Soc. 2007, 129, 3348-3357. (b) P.C. A. 

Bruijnincx and P. J. Sadler, Adv. Inorg. Chem. 2009, 61, 1-62. 

3. S. Schäfer, I. Ott, R. Gust, W. S. Sheldrick, Eur. J. Inorg. Chem. 2007, 3034-3046. 

90

P-33 


The Research of the Interaction between Quercetin and Zirconium (IV) in 

Water-Ethanol Medium 

Olessya Loiko, a A.Khalitova, a B.Tuleuov, b A.Mashentseva *c 

a Karaganda State University, Faculty of Chemistry, Department of Chemistry, Universitetskaya 28, 

100000, Karaganda, Kazakhstan. b ISPH “Phytochemistry”,Gasalieva str.4 , 100000, Karaganda, 

Kazakhstan. c L.N.Gumilev Eurasian national university, Faculty of Chemistry, Department of 

Chemistry, Munajtpasova 5, 010008, Astana, Kazakhstan. 

E-mail: olessya0905@gmail.com 

It’s known, that the search of new compounds with radioprotective, antioxidant and hepatoprotective 

activities is carried out among flavonoids; 1 because of their structural molecule uniqueness they can 

hamper not only oxidising processes, but also make transfer of energy and migration of elementary 

particles at the irradiation. At the same time, examples of individual flavonoids (rutin and quercetin) 

and their derivatives’ usage in the medical practice are single, despite their wide variety, accessibility 

of their production sources and relative availability. 

It is suggested that the biological activity of an organic ligand can be increased when co-coordinated 

or mixed with suitable metal ion, because of its ability to act as a free radical acceptor. 2 From the 

pharmacology point of view zirconium (IV) complexes are noted for their significant biological 

properties, namely antibacterial and antifungal activities. Information about mechanism of interaction 

between zirconium (IV) and quercetin will help to explain and predict biochemical activity of these 

components’ mixture in the medical product. 

The ability to form complex between quercetin and zirconium (IV) was studied in this work using 

spectrophotometer method. Quercetin zirconium (IV) complex is characterized by 3 absorption bands: 

in UV and visible parts of spectrum at 360 nm, 395 nm and 475 nm; the extension coefficients (ε) 

were calculated for these bands: 1042, 1045 and 2966 correspondingly. In the presence of metal ions, 

a bathochromic shift on 55 nm is observed in the absorption spectra of complex. Such bathochromic 

shift can be explained by the interaction of cobalt chloride with the free C3-oxo group of quercetin. 

Investigated complex was synthesized in the solid state. IR spectra of ligand and complex present 

evidence of the coordination between zirconium ions and oxo-group of quercetin. It can be noted that 

Zr-O frequencies appear at 559.78, 538.53 and 472.02cm -1 . 

As the result of made researches of complex formation between zirconium (IV) and quercetin, the 

influence of time, solvent and organic reagent concentration were studied. Studying the complex 

solubility, it was determined that the compound sufficiently dissolves in water-ethanol mixture. It has 

been shown, that if the content of ethanol is under 15%, the complex will fall in a precipitation. Using 

Jobs method it was established, that made compound has content, which formula is C30H18O15Zr. The 

stability constant of complex is (9,56 ± 0,01)·10 9 , this number shows that the complex is averagely 

stable. Complex forms at the room temperature. 

According to the PASS biocsreening calculation follow activities for the synthesized complex are 

antiparkinsonian, nootropic, cardioprotectant and creatine kinase inhibitor. 

References 

1. I.S. Vasil’eva, V.A. Paseshnichenko, The achievements of Biological Chemistry, 2000, 3, 153-156. 

2. M.Y. Morandi, J. Pourahmad, Free Radic. Biol. Med. 2003, 34, 243‐250. 

91

P-34 


Photocytotoxicity and DNA Cleavage Activity of 2-Ferrocenyl Adducts having 

Imidazophenanthroline and Imidazophenanthrene Moieties 

Basudev Maity, a Mithun Roy, a Sounik Saha, a Ritankar Majumdar, b Rajan R. Dighe, b and Akhil R. 

Chakravarty* a 

a Indian Institute of Science, Department of Inorganic and Physical Chemistry, b Department of 

Molecular Reproduction, Development and Genetics, Sir C V Raman avenue, 560012, Bangalore, 

India. E-mail: basudev@ipc.iisc.ernet.in 

Ferrocene is an important constituent in the field of bioorganometallic chemistry related to nucleic 

acids in spite of having any effective anticancer activity. 1 It is the ferrocenium cation, the oxidized 

form of ferrocene, which is responsible for the anticancer activity. 2 The designing of new ferrocenebased 

molecules showing photo-induced DNA cleavage and/or photocytotoxic activities are of 

interests for their potential applications in the field of molecular biology, biotechnology and 

particularly in medicine. This presentation includes the synthesis, characterization, interactions with 

DNA, photo-induced DNA cleavage activity and photocytotoxicity of 2-ferrocenylimidazophenanthroline 

(1) 3 and 2-ferrocenyl-imidazophenanthrene (2). To understand the role of the 

ferrocenyl moiety, 2-phenyl-imidazophenanthroline (3) 4 has been studied as a control species. 

Compound 2 has been characterized by X-ray crystallography. The interaction of the compounds with 

DNA has been studied by UV-visible absorption titration and thermal denaturation methods. All the 

compounds show good binding affinity to calf thymus DNA with intrinsic binding constant values of 

~10 5 M -1 . The thermal denaturation data suggest DNA groove binding nature of the compounds. They 

show poor chemical nuclease activity in the presence of H2O2 as an oxidizing agent and are inactive in 

the presence of cellular reducing agent glutathione. Compound 1 shows significant photo-induced 

DNA cleavage activity in UV-A light of 365 nm and visible light of 488 (blue light) and 530 nm 

(green light). The mechanistic investigations of the DNA cleavage activity reveal the involvement of 

reactive oxygen species. The photocytotoxicity of the compounds in human cervical HeLa cancer cell 

line has been studied in UV-A light of 365 nm. 

References 

1. D. R. van Staveren, N. Metzler-Nolte, Chem. Rev. 2004, 104, 5931-5985. 

2. G. Tabbì, C. Cassino, G. Cavigiolio, D. Colangelo, A. Ghiglia, I.Viano, D. Osella, J. Med. Chem. 

2002, 45, 5786-5796. 

3. F. Zapata, A. Caballero, A. Espinosa, A. Tárraga, P. Molina, J. Org. Chem. 2008, 73, 4034–4044. 

4. N. M. Shavaleev, H. Adams, J. A. Weinstein, Inorg. Chim. Acta 2007, 360, 700–704. 

92

P-35 


Carbon Monoxide Release and Biological Properties of Manganese Tricarbonyl 

Trispyrazolyl Complexes 

Johanna Niesel, a Hendrik Pfeiffer, a and Ulrich Schatzschneider *a 

a Ruhr-Universität Bochum, Lehrstuhl für Anorganische Chemie I, Universitätsstrasse 150, D-44801 

Bochum, Germany. E-mail: johanna.niesel@rub.de 

Carbon monoxide is an important small molecule messenger in the human body. 1 For its controlled 

release to biological systems, transition metal carbonyl complexes can be utilized to exploit the 

beneficial physiological effects of CO like vasodilatation and protection against oxidative stress. In 

addition, cytotoxic activity of carbon monoxide against cancer cells and pathogenic microorganisms 

has been established. In contrast to hydrolytic liberation of CO from metal carbonyl complexes, 

photoactivated CO release will allow for a precise spatial and temporal control of its biological 

activity. 2 Recently, we have identified [Mn(CO)3(tpm)] + with tpm = tris(1-pyrazolyl)methane as a 

stable in aqueous solution and inactive against cancer cells in the dark. However, upon light activation 

it efficiently kills HT29 human colon cancer cells. 3,4 To study the influence of the ligand system on the 

CO release and the biological properties, manganese trispyrazolylcomplexes with variations on the 

pyrazol rings 6 or the alpha carbon 7 were synthesized and their CO release efficiency as well as 

biological activity against human breast cancer cells MCF7 and colon cancer cells HT-29 was 

investigated. 

References 

1. S.W. Ryter, J. Alam, A.M.K. Choi, Physiol. Rev. 2006, 583-650. 

2. U. Schatzschneider, Eur. J. Inorg. Chem. 2010, 10, 1451-1467. 

3. J. Niesel, A. Pinto, H. W. Peindy N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem. 

Commun. 2008, 1798-1800. 

4. H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider, Dalton Trans. 2009, 4292-4298. 

5. K. Meister, J. Niesel, U. Schatzschneider, N. Metzler-Nolte, D.A. Schmidt, M. Havenith, Angew. 

Chem. 2010, 122, 3382-3384; Angew. Chem. Int. Ed. 2010, 49, 3310-3312. 

6. D.L. Reger, R.D. Sommer, J. Organomet. Chem. 2000, 607, 120-128. 

7. B.J. Liddle, J.R. Gardinier, J. Org. Chem. 2007, 72, 9794-9797. 

93 

c(MbCO) in µM 

30 

20 

10 

0 

0 50 100 

t(min)

P-36 


Novel Polypyrrole Substituted Carbon Monoxide Releasing Molecules 

(CO-RMs); New Delivery System for Carbon Monoxide 

Niall B. McGuinness, a Carmel B. Breslin, a and A. Denise Rooney a 

a Environmental Technologies and Biomaterials Research Group, Department of Chemistry, 

National University of Ireland, Maynooth, Co. Kildare, Ireland. Email: niall.b.mcguinness@nuim.ie 

Research has shown that minute quantities of carbon monoxide (CO) molecules produced in the 

human body are a fundamental component for life processes, but in larger doses the inherent toxic 

nature of CO cannot be ignored. However, CO liberated from CO-RMs can be accurately controlled 

and delivered at precise concentrations. Beneficial actions of CO include cardioprotection against 

blood flow restriction, heart attack and cardiac graft rejection; prevention against the increase of 

strength in muscle contraction of the heart; and suppression of the inflammatory response 1 . A problem 

associated with several of the CO-RMs is the transition metal (T.M.) employed, which can be toxic 

due to accumulation in the human body. 

N 

N 

O 

O 

N 

H 

N 

H 

N N 

4,4'-Bis-(N -propyl-3-pyrrole-carbamoyl)-2,2'-bipyridine 

1 

Figure 1: Novel substituted pyrrole monomer and metal complex synthesised. 

OC 

OC 

94 

CO 

Mo 

CO 

N 

N 

O 

O 

N 

H 

N 

H 

N N 

Tetracarbonyl (4,4'-bis-(N-propyl-3-pyrrole-carbamoyl)-2,2'-bipyridine) 

molybdenum (0) 

We have set out to bind T.M. carbonyl complexes to polypyrrole, a biocompatible conducting 

polymer. The carbonyl complex is trapped in the polymer so that after CO is released into the tissue 

the complex can then be removed. The monomer unit 1 has been synthesised and successfully 

undergoes electrochemical polymerization. Mo(CO)4 has been complexed to this monomer at high 

yield using a microwave-assisted method. Before investigating the electrochemical response of the 

polymer formed from complex 2, studies were carried out on 2 in solution. Electrochemical studies 

indicate that upon 1-electron oxidation, Mo(CO)4(bipy-pyr) undergoes CO subsitution in a 

coordinating solvent (Figure 2). Direct evidence that the oxidation results in CO release was provided 

by studies performed using an Optically Transparent Thin-Layer Electrochemical (OTTLE) cell with 

IR detection. Our results indicate that this is a promising approach for the controlled release of CO 

from a polymer. 

0.0002 

0.0001 

I (Amps/cm 2 ) 

0 

Black: redox couple of Mo(CO) 4(bpy‐pyr) 

in DCM 

Grey: redox couple of Mo(CO) 4(bpy‐pyr) 

in DCM with 3 eq. of MeCN present 

*1‐electron oxidation and reduction 

of Mo(CO) 4(bpy‐pyr) 

Loss of reduction peak 

caused by rapid CO 

substitution due to 

-0.0001 

* presence of MeCN 

0 0.25 0.50 0.75 1.00 1.25 

Figure 2: Cyclic voltammograms of Mo(CO)4(bipy-pyr) in DCM and MeCN. 

References 

E (Volts) 

1. R. Foresti, M. G. Bani-Hani, R. Motterlini Intensive Care Med. 2008, 34, 649-658. 

* 

2

P-37 


Cytotoxicity Studies on Rhenium(I) Tricarbonyl Complexes 

Teck-Tian Wong, Li-Peng Wong, Peng-Foo Peter Lee and Yaw-Kai Yan* 

Nanyang Technological University, National Institute of Education, Natural Sciences & Science 

Education Department, 1 Nanyang Walk, Singapore 637616. E-mail: yawkai.yan@nie.edu.sg 

Since the late 1980’s, there has been a steady growth of interest in ruthenium anti-cancer drugs as 

reflected in the accelerating growth of publications in this area. 1 In particular, a series of water soluble 

and stable ruthenium(II) arene ethylenediamine complexes (1) was shown to exhibit promising anticancer 

activity in vitro and in vivo. 2 Anti-cancer activity has also been observed in rhenium(I) 

tricarbonyl complexes. 3 Since both rhenium(I) and ruthenium(II) are d 6 configuration metal ions, it 

would be interesting to investigate the anti-cancer activity of rhenium(I) tricarbonyl complexes with 

N,N- and P,P- chelating agents. The three CO ligands of the Re(I) complexes correspond to the arene 

ligand of the Ru(II) complexes in that both donate six electrons. The chelating N,N- and P,P- ligands 

of the Re(I) complexes correspond to the ethylenediamine ligand of the Ru(II) complexes and both 

types of complexes have a single ligand exchange site occupied by a monoanionic ligand. 

In this study, we are concerned with the synthesis and bio-physicochemical characterization of a series 

of mononuclear rhenium(I) tricarbonyl complexes [Re(X)(CO)3L2] (2) [where X = Br, Cl, Cl2HCCO2; 

L2 = ethylenediammine (en), N,N,N ′ ,N ′ -tetramethylethylenediamine (tmen), 2,2 ′ -bipyridine (bpy), 

N,N ′ -dimethylethylenediamine (dmen), 2,2 ′ -bipyridine-4,4 ′ -dicarboxylic acid (H2bpdc), 

1,3-bis(diphenylphosphino)propane (dppp) and 1,1′-bis(diphenylphosphino)ferrocene (dppf)]. All the 

complexes were characterized by IR and 1 H NMR spectroscopy and elemental analysis. The rhenium 

complexes and their respective ligands were screened using the human leukaemia (MOLT-4) cell line 

via the MTT assay. The results will be presented in the poster. 

References 

Cl 

Ru 

N 

N 

R 

+ 

95 

OC 

OC 

Re 

1 2 

1. A. Levina, A. Mitra, P. L. Lay, Metallomics 2009, 1, 458-470. 

2. Y. K. Yan, M. Melchart, A. Habtemariam, P. J. Sadler, Chem. Commun. 2005, 4764-4776. 

3. (a) J. Zhang, J. J. Vittal, W. Henderson, J. Wheaton, I. H. Hall, T. S. A. Hor, Y. K. Yan, J. 

Organomet. Chem. 2002, 650, 123-132. (b) Y. K. Yan, S. E. Cho, K. A. Shaffer, J. E. Rowell, B. J. 

Barnes, I. H. Hall, Pharmazie 2000, 55, 307-313. (c) W. Wang, Y. K. Yan, T. S. A. Hor, J. J. Vittal, J. 

R. Wheaton, I. H. Hall, Polyhedron 2002, 21, 1991-1999. 

X 

L 

CO 

L

P-38 


Bioorthogonal Coupling Strategies in the Synthesis of CORM-peptide Conjugates 

a 

Hendrik Pfeiffer, a Johanna Niesel, b and Ulrich Schatzschneider* a 

Ruhr-Universität Bochum, Department of Chemistry and Biochemistry, 

Universitätsstrasse 150, 44801 Bochum, Germany, hendrik.pfeiffer@rub.de 

In the human body carbon monoxide possesses versatile properties as a signalling mediator and 

participates in important biological processes. Beside being a potent vasodilator, CO can exert antiinflammatory, 

anti-apoptotic, and anti-proliferative effects. 1,2 Since it is a toxic gas and difficult to 

handle, there is considerable interest in the development of CO releasing molecules (CORMs) as 

"solid storage forms" for carbon monoxide. Therefore, transition metal carbonyl complexes are highly 

interesting target structures. 3 Compared to thermally induced liberation of CO, photoactivated CO 

release will allow for a precise spatial and temporal control of its biological action. 4 We have recently 

synthesized several tungsten, molybdenum, and manganese complexes with bidentate as well as 

tridentate nitrogen donor ligands as promising new photoCORMs, which are inert in the dark in 

aqueous solution, but release CO upon irradiation. 5 

Carrier peptides are important vehicles to achieve accumulation of bioactive cargos in specific 

biological target sites. Thus, we have explored the functionalization of the parent photoCORMs with 

model peptides using bioorthogonal coupling strategies, such as oxime ligation, Sonogashira crosscoupling, 

or the alkyne-azide 1,3-dipolar cycloaddition (click reaction). 6 

References 

1. S. W. Ryter, J. Alam, A. M. K. Choi, Physiol. Rev. 2006, 86, 583-650. 

2. T. R. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green, R. Motterlini, Angew. Chem. Int. Ed. 

2003, 42, 3722-3729. 

3. J. Boczkowski, J. J. Poderoso, R. Motterlini, Trends Biochem. Sci 2006, 31, 614-621. 

4. U. Schatzschneider, Eur. J. Inorg. Chem. 2010, 1451-1467. 

5. J. Niesel, A. Pinto, H. W. Peindy N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem. 

Commun. 2008, 1798-1800. 

6. H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider, Dalton Trans. 2009, 4292-4298. 

96

P-39 


Metallocarbonyl Complexes of Bromo- and Dibromomaleimide. Synthesis and 

Reactions with Cysteine Derivatives 

Bogna Rudolf, a* Marcin Palusiak, b and Emilia Fornal c 

a Department of Organic Chemistry, University of Łódź, Tamka 12, Łódź 91-403, Poland, 

b Department of Crystalography and Crystal Chemistry, University of Lodz, Tamka 12, 

Łódź 91-403, Poland 

c Chemistry Department, Faculty of Mathematics and Life Sciencies, The John Paul II Catholic 

University of Lublin, al. Krasnicka 102, 20-718 Lublin, E-mail:brudolf@chemia.uni.lodz.pl 

The maleimide motif is widely used for the selective reactions with thiols and there are numerous N– 

functionalized maleimide reagents applied for cysteine modification. Among them the (η 5 - 

C5H5)M(CO)x(η 1 -N-maleimidato) (M = Fe, x = 2; M = W, Mo, x = 3) markers were reacted 

with cysteine containing peptides and proteins. These metallocarbonyl complexes display 

characteristic strong absorption bands in their IR spectra, �C≡O, appearing in the 1950-2060 

cm -1 spectral region, which is usually free of any absorption of biomolecules or biological 

matrices. 1,2 

Recently it was reported that the bromomaleimide and its derivatives are of interest for 

bioconjugation and reversible cysteine modification. 3,4 

Fe 

OC 

OC 

cysteine derivatives 

In this communication, synthesis of metallocarbonyl derivatives of bromo- and dibromomaleimide 

(e.g. 1) along with reactions of these complexes with cysteine derivatives will be presented. 

References 

O 

1 

N 

O 

Br 

HS 

1. B. Rudolf, J. Zakrzewski, Tetrahedron Lett. 1994, 35, 9611-9612. 

2. B. Rudolf, M. Palusiak, J. Zakrzewski, M. Salmain, G. Jaouen, Bioconjugate Chem. 2005, 16, 1218- 

1224. 

3. L. M. Tedaldi, M. E. B. Smith, R. I. Nathani, J. R Baker, Chem. Com. 2009, 43, 6583-6585. 

4. M. E. B. Smith, F. F. Schumacher, C. P. Ryan, L. M. Tedaldi, D. Papaioannou, G. Waksman, 

S. Caddick, J. R. Baker J. Am. Chem. Soc. 2010, 132, 1960-1965. 

97 

OC OC 

Fe 

O 

N 

O 

S

P-40 


Molybdenum Carbonyl Complexes as CO Releasing Molecules 

Lukas Kromer a and Carlos Romão* a,b 

a ITQB-UNL, Av. da República, Estação Agronómica Nacional, 2780-157 Oeiras, Portugal. 

b ALFAMA Lda., Taguspark, Núcleo Central 267, 2740-122 Porto Salvo, Portugal. 

E-mail: kromer@itqb.unl.pt 

Carbon Monoxide (CO) is an essential signalling molecule produced in the body. Endogenous 

overproduction of CO in pathological situations strongly suggests medicinal applications for CO. 

Rather than using CO gas; drug research is focused on the development of CO-releasing Molecules 

(CO-RMs). 1 Although there are a large number of CO-RMs known, few if any fulfil the essential 

criteria for use as drugs, such as solubility in aqueous solutions of physiological pH, stability during 

storage and controlled release of CO in vivo, and efficacy at non-toxic doses. Furthermore, targeting of 

specific tissue is desirable. To obtain water-soluble organometallic complexes, they either have to be 

charged or contain ligands that can be ionised in aqueous solutions through protonation or 

deprotonation. 

Charged complexes were synthesised with two types of ligands: 1,3-diketone and 2-hydroxyketone 

ligands. Both types of ligand can be deprotonated and form anionic complexes with the general 

structure (Et4N)[Mo(O-O)(CO)4]. 2 A second series of neutral complexes bearing functional groups 

were synthesised with several mono- and bidentate amine ligands in a conventional microwave. 3 

OC 

CO 

Mo 

O 

OC 

CO 

O 

R 

R 

0, 1 

- 

OC 

OC 

Mo 

CO 

CO 

R 2 

N 

N 

R 2 

OC 

CO 

Mo 

NHR 

OC 

CO 

NHR 

98 

4.00 

3.50 

3.00 

2.50 

O 

. 

C 2.00 

e 

q 

1.50 

1.00 

0.50 

0.00 

CO‐Hb formation in blood 

0 20 40 60 80 

time [min] 

The synthesised complexes were fully characterised and investigated in terms of solubility, 

stability in aqueous solution and the CO release rate was determined both in vitro by GC-TCD as in ex 

vivo assays in sheep blood with an Oxymeter. The direct measurement of CO-Hb levels in sheep blood 

gives you an immediate answer about CO release under biological conditions. The water soluble, 

neutral amine complexes exhibited a ligand-dependant CO release rate decreasing from primary, 

secondary to tertiary amine ligands with half life times between 15 and 60 minutes. In contrary, the 

results from the non water soluble amine and the less stable anionic complexes showed the limitation 

of the setup, in which the solubility and stability under physiological conditions is crucial. In 

conclusion, complexes with tuneable CO release rates are accessible and led to further improvements 

in terms of stability and solubility of CO-RM’s. 

References 

1. R. Motterlini, B. E. Mann, R. Foresti, Expert Opin. Invest. Drugs 2005, 14, 1305-1318. (b) S. W. 

Ryter, L. E. Otterbein, Bioessays 2004, 26, 270-280. (c) R. Motterlini, J. E. Clark, R. Foresti, P. 

Sarathchandra, B. E. Mann and C. J. Green, Circ. Res. 2002, 90, E17-E24. 

2. G. Doyle, J. Organomet. Chem 1973, 61, 235-245. 

3. M. Ardon, G. Hogarth, D.T.W. Oscroft, J. Organomet. Chem. 2004, 689, 2429-2435. 

a) 

b) 

c)

P-41 


Constrained Peptides Constructed by Coordination 

of Propargylcysteines with Tungsten 

Thomas A. McTeague, Zephyr D. Dworsky, and Timothy P. Curran* 

Department of Chemistry, Trinity College, 06106, Hartford, CT, USA. 

E-mail: timothy.curran@trincoll.edu 

In prior work we have demonstrated that alkynes can be appended to peptide carboxylic acids (via 

acylation with propargylamine) and amines (via acylation with propargylchloroformate), that peptides 

bearing two alkynes can be prepared, and that reaction of these dialkynylpeptides with W(CO)3(dmtc)2 

yields a cyclic peptide that incorporates the tungsten atom (which is called a metallacyclicpeptide). 1,2 

We have sought to use the tungsten-alkyne coordination to constrain peptides to specific threedimensional 

conformations; in one case peptide turns were constrained by the tungsten-alkyne 

coordination. 2 In an effort to create helical peptides we have appended alkynes to the side chain 

amines of lysines, and have constructed peptides having two of these alkynyllysines. Coordination of 

these dialkynylpeptides to tungsten has produced metallacyclicpeptides. Investigations using NMR 

spectroscopy has shown that these metallacyclicpeptides are too flexible to constrain the peptide to a 

specific conformation. In particular, in these metallacycles we have found that the two alkyne groups 

can rotate around the tungsten center, generating a number of conformational isomers in solution. 

We have hypothesized that appending the alkyne group to the side chain amine of lysine locates the �ligand 

too far from the peptide backbone for coordination to tungsten to constrain the peptide. 

Accordingly, we have begun investigations to see whether locating the alkyne group closer to the 

peptide backbone will make the complexes more rigid. Towards this end we have been investigating 

the use of propargylcysteine as our alkynylamino acid. Attractive features of propargylcysteine are 

that it can readily be prepared in multigram quantities from cysteine, and derivatives of 

propargylcysteine are easy to work with in peptide synthesis. 

This presentation will discuss the preparation of peptides possessing two propargylcysteines, the 

coordination of both alkynes in these peptides to tungsten, and the conformational analysis of the 

resulting metallacyclicpeptides. Particular emphasis will be on the study of compounds 1 and 2. 

References 

O 

H 

N 

H 

N 

O 

O 

NH 

S 

S 

1 

W(dmtc) 2 

99 

ButO N 

O 

N 

H 

N 

O 

H 

N 

O 

H 

H 

O 

CONHR 

S 

S 

2 

W(dmtc) 2 

1. T. P. Curran, R. S. H. Yoon, B. R. Volk, J. Organometallic Chem., 2004, 689, 4837-4847. 

2. T. P. Curran, A. B. Lesser, R. S. H. Yoon, J. Organometallic Chem., 2007, 692, 1243-1254.

P-42 


Characterisation of Zeise´s Salt - Analogues Regarding Cytotoxicity and Stability 

Sandra Meieranz a amdRonald Gust *a 

a Freie Universität Berlin, Institute of Pharmacy, Königin-Luise-Str. 2+4, 14195 Berlin, Germany. 

Platinum complexes are widely used in antitumor therapy. DNA is their main target in cells forming a 

covalent bond to the N7 position of guanine. The intolerable side effects and the acquired resistance 

during the therapy encouraged the synthesis of new platinum compounds to afford drugs with 

improved pharmacological properties and broaden antitumor activity. 1 Therefore, we synthesized 

Zeise´s Salts analogues and examined their cytotoxicity in comparison to cisplatin. The complexes 

were prepared according to literature procedures. 2 Zeise´s Salt is known as a water stable platinum 

complex. 

We tested the synthesized compounds on hormone dependent MCF-7 and hormone independent 

MDA-MB-231 breast cancer cell lines. The cytotoxicity was very low. Therefore, we determine the 

stability in aqueous solution using HPLC and LC-MS. Interestingly, the ester in our compounds is 

rapidly cleaved resulting in inactive degradation products. Further investigations on the stability are of 

interest to get stabile Zeise´s Salt analogue platinum complexes. 

References 

1. Wong, E.; Giandomenico, C. M. Chem. Rev. 1999, 99, 2451. 

2. Chock, P. B.; Halpern, J.; Paulik, F. E. Inorg. Syn. 1973, 14, 90. 

100

P-43 


Bengin Reactions with Acetylferrocene for the Synthesis of some 

Ferrocenylhydrazones of Expected Biological Activity 

Mohamed A. Metwally *a 

a Chemistry Department, Faculty of Science, University of Mansoura, P.O. Box 23, Mansoura, Egypt. 

Email: mamegs@mans.edu.eg 

Waste-free environmentally benign solid-state reactions means 100% yield of one product without any 

necessity for purifying workup by recrystallization, chromatography, etc. Continuing our earlier 

studies on ferrocenes, 1,2 the solid state reaction of acetylferrocene using the ball-milling technique 

with several hydrazines and hydrazides resulted in the formation of the hydrazones 1 in quantitative 

yields (95-98%). The products were screened for their antibacterial and antifungal activities and gave 

promising results. 

References 

Fe 

1. M.A. Metwally, E.E.M. Kandel, F.A. Amer, J. Indian Chem. Soc. 1987, 64, 517-518. 

2. M.A. Metwally, F.A. Amer, J. Indian Chem. Soc. 1988, 65, 51-53. 

CH 3 

C 

101 

N.NH.R 

1, a, R= -C 6H 5NO 2-p, 

b, R= -C 6H 3(NO 2) 2-2,4-, 

c, R= -SO 2C 6H 5, 

d, R= -CSNH 2, 

e, R= -COCH 2CN

P-44 


Ferrocenyl Flavonoids: A Novel Class of Cytotoxics 

Jean-Philippe Monserrat, a Elizabeth A. Hillard, a and Gérard Jaouen *a 

a Organometallic Medicinal Chemistry Team, UMR 7223, Laboratoire Charles Friedel 

11, rue Pierre et Marie Curie 

75231 Paris Cedex 05 

Occupying the second step of the mortality podium in the western countries, cancer has become one of 

the most widely studied diseases in the world, and one of the most challenging targets for scientists. In 

order to combat the common problem of drug resistance, we have decided to approach the problem via 

the redox machinery of the cell. It is now accepted that elevated levels of cellular oxidative stress and 

dependence on ROS-signaling for mitosis and apoptosis represent a specific vulnerability of cancer 

cells that can be targeted by redox modulators. 1 

Ferrocene is an organometallic complex that possesses a stable and reversible redox couple, and 

possesses many attractive qualities for use in medicinal chemistry. Ferrocene-tamoxifen derivatives, in 

particular, are known to be highly toxic against cancer cells via a redox mechanism. 2 

Fe 

O 

OH 

hydroxyferrocifen 

N 

102 

O 

OH O 

quercetin 

Flavonoids are a large class of natural products, some of which are active against cancer and are 

thought to act, at least partially, via a redox mechanism. For instance, quercetin, in the process of 

scavenging free radicals, can be converted to four quinone forms (QQ), which can form adducts with 

glutathione, thus disturbing the redox balance of the cell. 3 Other polyphenols specifically act as 

prooxidants in oxidizing environments. 4 Because some cancer cells are under oxidative stress, these 

properties could be useful in the design of selective cancer agents. 5,6 By the introduction of ferrocene, 

we hope to modulate the flavonoids’ redox properties and enhance their antiproliferative effects. 

We have recently discovered a novel reaction which gives easy access to the first reported ferrocenyl 

flavones. Preliminary results show that the antiproliferative effects of ferrocene flavones against the 

highly aggressive B16 mouse melanoma cell line are considerably stronger than those of organic 

flavones, with IC50 values in the low micromolar range. The synthesis and biological results of this 

original class of molecules will be presented. 

References 

1. G. T. Wondrak, Antiox. Redox. Sign. 2009, 11, 3013-3069. 

2. E. A. Hillard, A. Vessières, L. Thouin, G. Jaouen and C. Amatore, Angew. Chem. Int. Ed. 2006, 

45, 285-290. 

3. W. Boots, H. Li, R. P. F. Schins, R. Duffin, J. W. M. Heemskerk, A. Bast and G. R. M. M. 

Haenen, Toxicol. App.Pharmacol. 2007, 222, 89-96. 

4. Simić, D. Manojlović, D. Šegan and M. Todorović, Molecules, 2007, 12, 2327. 

5. H. Pelicano, D. Carney and P. Huang, Drug Resist. Update 2004, 7, 97-110. 

6. Hoffman, L. M. Spetner and M. Burke, J. Theor. Biol. 2001, 211, 403-407. 

HO 

OH 

OH 

OH

P-45 


Octahedral Ruthenium Complexes as Phosphatidyl-inositol-3-kinase Inhibitors 

Stefan Mollin, a Jie Qin, b Ronen Marmorstein b and Eric Meggers *a 

a Philipps-Universität Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35032, Marburg, 

Germany. b The Wistar Institute, 3601 Spruce Street, 19104, Philadelphia, PA, USA. 

E-mail: stefan.mollin@chemie.uni-marburg.de 

The design of bioactive compounds for applications in medicinal chemistry and chemical biology is 

focused predominantly on organic molecules, whereas inorganic compounds are mainly known for 

their reactivity (e.g. cisplatin) or imaging properties (e.g. gadolinum complexes in MRI). 1 However, in 

recent years, MEGGERS et al. developed a novel strategy, wherein inert ruthenium(II) complexes were 

designed as protein kinase inhibitors. 2 Here, the ability of metal complexes is used to organize organic 

ligands in three-dimensional space to form structures with unique and defined shapes. Based on the 

natural product staurosporine 1, a potent but unselective kinase inhibitor, MEGGERS et al. designed 

half-sandwich complexes initially and achieved a number of potent and selective inhibitors. 

Phosphatidyl-inositol-3-kinases (PI3Ks) are a family of lipid kinases which act as signal transducers. 

They serve phosphatidylinositol-3,4,5-triphosphate (PIP3), an important second messenger which 

recruits AKT/PKB. Disruption of the PI3K signaling pathway leads to uncontrolled cell proliferation, 

survival, and cell growth. Thus, PI3K is a highly attractive target for the development of therapeutic 

agents to treat cancer and other related diseases. 

MARMORSTEIN and MEGGERS et al. found that a methylation of the pyridocarbazole-imide leads to a 

selectivity switch between protein and lipid kinases. Whereas half-sandwich complexes with free 

imides were found as nanomolar GSK-3 and Pim-1 inhibitors, complex 2 shows good selectivity for 

PI3Ks. 3 To further increase the potency and selectivity our focus has shifted now to octahedral 

compounds 3 with even more defined and rigid shapes. Following this strategy more potent inhibitors 

have been synthesized with up to tenfold selectivity between the different isoforms PI3Kα and PI3Kγ. 

References 

1. C. Orvig, M. J. Abrams, Chem. Rev. 1999, 99, 2201-2204. 

2. (a) H. Bregman, P. J. Carroll, E. Meggers, J. Am. Soc. 2006, 128, 877-884. (b) E. Meggers, G. E. 

Atilla-Gokcumen, H. Bregman, J. Maksimoska, S. P. Mulcahy, N. Pagano, D. S. Williams, Synlett 

2007, 8, 1177-1189. 

3. X. Peng, D. S. Williams, G. E. Atilla-Gokcumen, L. Milk, X. Min, K. S. M. Smalley, M. Herlyn, E. 

Meggers, R. Marmorstein, ACS Chem. Biol. 2008, 3, 305-316. 

103

P-46 


New Topoisomerase II Poisons 

Matthew P. Akerman, a Mark T. Muller, b and Orde Q. Munro* a 

a University of KwaZulu-Natal, School of Chemistry, AuTEK Biomed, Private Bag X01, Scottsville, 

Pietermaritzburg, South Africa. b University of Central Florida, College of Medicine, Biomolecular 

Research Annex, 12722 Research Parkway, 32826-3227, Orlando, FL, USA. 

E-mail: munroo@ukzn.ac.za 

DNA topoisomerase II (topo II) is a well-established anticancer drug target. We have identified novel 

metallo-drugs that act specifically on topo IIA. Topo II enzymes are essential for life and are primarily 

responsible for decatenation of daughter chromatids during mitosis. 1 To function as a decatenase, topo 

II makes a transient double strand DNA break, providing an enzyme/DNA gate through which a distal 

duplex strand may pass. 1 The DNA cleavage intermediate is unique since a covalent DNA-topo II 

complex exists during the trans-esterification at the site of the break. Compounds that react with this 

transient intermediate, forming a ternary DNA-enzyme-drug complex, can arrest or poison the 

cleavage/religation cycle, inducing permanent DNA breaks, thereby damaging the genome of the 

target cell. Acute cytotoxicity results as the cell accumulates double strand DNA breaks. Drugs that 

induce breaks are topo II poisons and are generally excellent anti-cancer agents. 

We have synthesized and fully characterized a series of crystalline d 8 coordination compounds with 

tetradentate ligands. The compounds were screened by the National Cancer Institute (NCI, USA) 

against their panel of 60 human cancer cell lines. The most active compound is chiral, has a mean IC50 

of 14(2) �M, and is more cytotoxic than cisplatin (mean IC50 = 27 �M). Some cancer cell lines were 

substantially more susceptible to the new compounds than to cisplatin (ca. 12–30% of the cell lines 

tested, depending on the compound used). Statistical comparison of the ex vivo data for the most active 

compounds with drugs having known modes of action in the NCI database indicated that the cellular 

target is most likely topo II. This prediction was confirmed by in vitro DNA cleavage experiments 

using purified topo I and II and supercoiled DNA substrate. The data indicate that the compounds act 

as poisons at low concentrations (best current EC50 ∼ 1 �M) and as catalytic inhibitors at higher 

concentrations (typical EC50 ∼ 20–30 �M). The compounds are specific for topo II and do not target 

topo I, even at high concentrations. In vivo experiments are currently underway to assess whether the 

compound can target topo II in a chromatin setting. Preliminary data demonstrate that topo I is not 

being targeted in the cancer cell lines tested. 

Some of the compounds hydrolyze in aqueous buffer to generate metal-hydroxo derivatives. All 

hydrolysis-inert compounds bind calf thymus DNA (pH 7 phosphate buffer, 37 �C) with association 

constants ranging from 1.43(3) × 10 5 to 1.01(4) × 10 6 M –1 . The compounds with a high affinity for calf 

thymus DNA were all active cytotoxic agents in the NCI-60 screen. Reduction of the compounds by 

cellular levels of glutathione (pH 7 phosphate buffer, 37 �C) was followed by visible spectroscopy. 

Loss of the metal-to-ligand charge transfer (MLCT) band and appearance of the �–�* band of the free 

ligand confirmed reductive demetallation of the chelate in each case. The kinetics had second-order 

rate constants ranging from 0.0463(2) to 0.301(7) M –1 s –1 . Importantly, the most active compounds in 

the NCI-60 screen had the slowest reduction kinetics. Several structure–activity relationships for this 

new class of topoisomerase II poison have thus been delineated. A provisional patent has been filed 

and toxicology screens on the most active compounds have been scheduled. 

Acknowledgements: We thank AuTEK Biomed (Mintek and Harmony) for permission to publish selected data 

and financial support, the Department of Science and Technology (SA-COST EU Reciprocal Agreement) for a 

travel grant, and the Developmental Therapeutics Program (NCI, USA) cytotoxicity screens. 

References 

1. K. C. Dong, J. M. Berger, Nature 2007, 450, 1201-1205. 

104

P-47 


Organometallic Ruthenium and Osmium Complexes with Carbohydrate-Based 

Ligands as Anticancer Agents 

Alexey A. Nazarov, a * Muhammad Hanif, b Lucienne Juillerat-Jeanneret, a Christian G. 

Hartinger, b Olivier Zava, a Michael A. Jakupec, b Bernhard K. Keppler, b Paul J. Dyson a 

a Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 

CH-1015 Lausanne, Switzerland. 

b University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, 

Austria.E-mail: alexey.nazarov@epfl.ch 

Half-sandwich organometallic compounds have attracted increasing interest due to their potential as 

anticancer drugs. 1 Different approaches have been explored, including mono- and bifunctional 

compounds such as RAPTA compounds, targeted approaches, kinase inhibitors, ruthenium-arene 

clusters and polynuclear ruthenium arene compounds. Increase of glucose uptake in malignant cells 

due to upregulation of glycolysis and glucose transporters in comparison to healthy cells is almost 

universal for cancer cells. Attaching a carbohydrate moiety to a Ru or Os center provides new metalbased 

compounds that exploit the biochemical and metabolic functions used for sugars in living 

organisms for transport and accumulation. 2,3 

This presentation will focus on synthesis of new sugar containing ruthenium(II) and osmium(II)–arene 

complexes and their characterization in terms of stability and cytotoxicity. The structural modification 

with regard to the arene ligand, the leaving group, and the nature the metal centers is discussed. 

The authors are indebted to the EU for a Marie Curie Intra European Fellowship within the 

7th European Community Framework Programme project 220890-SuRuCo (A.A.N.) and the 

Higher Education Commission of Pakistan (M.H.). 

References 

1. C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391-401. 

2. C. G. Hartinger, A. A. Nazarov, S. M. Ashraf,; P. J. Dyson, B. K. Keppler, Curr. Med. Chem., 

2008, 15, 2574-2591. 

3. I. Berger, M. Hanif, A. A. Nazarov, C. G. Hartinger, R. O. John, M. L. Kuznetsov, M. Groessl, F. 

Schmitt, O. Zava, F. Biba, V. B. Arion, M. Galanski, M. A. Jakupec, L. Juillerat-Jeanneret, P. J. 

Dyson, B. K. Keppler, Chem. Eur. J. 2008, 14, 9046 – 9057. 

105

P-48 


Cytotoxic Organoiridium(III) mono- and bis-intercalators with rigid bridging 

ligands of different lengths 

Ali M. Nazif a and William S. Sheldrick *a 

a Lehrstuhl für Analytische Chemie, Ruhr-Universität Bochum, D-44780 Bochum 

We have recently reported significant in vitro activity for members of the organometallic halfsandwich 

series [(η 5 -C5Me5)IrCl(pp)] + containing a single polypyridyl ligand (pp = dpq, dppz, dppn). 

Their IC50 values towards human MCF-7 (breast carcinoma) and HT-29 cells (colon-carcinoma) lie in 

the range 30.3 - 0.12�M and correlate with the size of the polypyridyl ligand, i.e. the IC50 values 

decrease significantly in the order dpq > dppz> dppn. 

An attractive design strategy to enhance both the affinity and specificity of DNA interactions is to 

combine an intercalator with other functionalities such as a second intercalator or a metal fragment 

capable of coordinative binding to nucleobases. Bis-intercalators might be expected to exhibit a 

greatly increased binding affinity for DNA, which could also lead to improved cytotoxicity owing to 

both the increased number of DNA adducts formed and decreased effectiveness of DNA repair 

proteins. 

These considerations prompted us to investigate the suitability of rigid bridging ligands of different 

lengths including pyrazine, 4,4'-bipyridine, trans-1,2-bis(4-pyridyl)ethylene and 1,2-bis(4pyridyl)ethyne 

for enabling bis-intercalation of the polypyridyl ligands belonging to the dinuclear 

complexes [{(η 5 -C5Me5)Ir(pp)}2(B)](CF3SO3)4 (pp = dpq, dppz, dppn). The interaction of the 

complexes with DNA was studied using UV/VIS spectroscopy, circular dichroism, viscosity titrations 

and gel electrophoresis. The studies confirm dppz as representing an optimum surface area for 

intercalation. In contrast, the dppn-containing complexes prefer surface binding with π-stacking. 

Based on these results, our research has focused on dppz-containing complexes which exhibit high 

cytotoxicities towards the human cell lines MCF-7 (breast cancer) and HT-29 (colon cancer), with 

IC50 values of respectively 3.1 �M and 3.7 �M being observed for the cell lines for B =4,4´-bipyridyl. 

Bis-intercalation of the 4,4´-bipyridyl complex was indicated by CD measurements and confirmed by 

viscosity titration, where the degree of DNA lengthening was doubled in comparison to an analogous 

monointercalator. 1 

Conclusive evidence for the bis-intercalative binding mode of [{(η 5 -C5Me5)Ir(dppz)}2(4,4´bpy)](CF3SO3)4 

was also obtained from an NMR-NOESY study of its interaction with the 

decanucleotide d(5´-CGCGTAGGCC-3´). The observed interruptions of intramolecular NOE cross 

peaks between nucleobase H6/H8 protons and sugar H2´/H2´´ protons of the preceding nucleobase are 

in accordance with a bis-intercalation mode sandwiching the G4/C17 and T5/A16 base pairs. A range 

of intermolecular NOE cross peaks are also observed between the dppz complex and decanucleotide 

protons. These include contacts between the H3 and H4 protons of one dppz ligand to T5-H2´ and 

between the H3´ and H4´ protons of the other dppz ligand to C17-H2´. The presence of these and other 

NOE cross peaks underlines the degree of detailed information that can be obtained from the NOESY 

spectrum, and allows a satisfactory refinement of the NMR structure of the complex-DNA adduct. 

References 

1. M.A. Nazif, J.-A. Bangert, I. Ott, R. Gust, R. Stoll, W. S. Sheldrick, J. Inorg. Biochem. 2009, 103, 1405- 

1414. 

106

P-49 


Bioinspired Catalysts With Bifunctional P,N - Ligands in Alkyne – Hydration 

Anna Louisa Noffke a and Peter C. Kunz *a 

a Department of Inorganic Chemistry I, Heinrich-Heine-University of Düsseldorf 

Universitätsstr. 1, D-40225 Düsseldorf, Email: anna-louisa.noffke@uni-duesseldorf.de 

Addition of water to terminal alkynes is a common path to carbonyl compounds. However, most 

synthetic strategies suffer from rather intense conditions or low selectivity. In nature, the 

tungstenoenzyme acetylene hydratase catalyzes the formation of ethanal from acetylene, for example 

in pelobacter acetylenicus. 1 For higher alkynes, the hydration-reaction can be equally accelerated 

using transition-metal catalysts with bifuntional ligands. 2 Systems similar to 1 (Fig. 1) perform with 

high yields and splendit selectivity. 2 

Fig. 1 Preparation of a Ru(II)-vinylidene complex and P,N-Ligands used. 

With ruthenium(II)-complexes of the general formula [(Cp)Ru(L)2Cl] (Cp = cyclopentadienyl) bearing 

our water-soluble, hemilabile P,N-ligands 3 (Fig. 1), catalytic activity in alkyne-hydration is observed 

under certain conditions. The first mechanistic steps of this reaction involve formation of vinylidene 

species which are subsequently aquated. In particular, the special role that is played by H-bonddonating 

and/or accepting ligand-functionalities within this catalytic process is explored in further 

detail. 

References 

1. S. Antony and C. A. Bayse, Organometallics 2009, 28, 4938–4944. (b) M. A. Vincent, I. H. Hillier, 

G. Periyasamy and N. A. Burton, Dalton Trans. 2010, 39, 3816–3822. 

3. (a) D. B. Grotjahn, D.A. Lev; J. Am. Chem. Soc. 2004, 126, 12232. (b) D.B. Grotjahn, Dalton 

Trans. 2008, 6497. 

2. (a) P. C. Kunz, M. U. Kassack, A. Hamacher, B. Spingler, Dalton Trans. 2009, 7741-7747. (b) P. C. 

Kunz, G. J. Reiß, W. Frank, W. Kläui, Eur. J. Inorg. Chem. 2003, 3945-3951. 

107

P-50 


A Tri-organometallic Derivative Containing a PNA Backbone: Synthesis and 

Antibacterial Activity 

Malay Patra, a Gilles Gasser, a# Dmytro Bobukhov, b Klaus Merz, a Alexander V. Shtemenko b 

Julia E. Bandow c and Nils Metzler-Nolte* a 

a Lehrstuhl für Anorganische Chemie I, Fakultät für Chemie und Biochemie, Ruhr-Universität 

Bochum, Gebäude NC 3 Nord, Universitätsstr. 150, 44801 Bochum, Germany; b Department of 

Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin Avenue 8, 

Dnipropetrovs'k, 49005 Ukraine; c Lehrstuhl für Biologie der Mikroorganismen, Fakultät für Biologie 

und Biotechnologie, Ruhr-Universität Bochum, Universitätsstr. 150, 44801 Bochum, Germany. # new 

address: Institute of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 

Zurich, Switzerland. 

Novel synthetic routes for the incorporation of different organometallic entities into the same 

biomolecule are highly demanded. With the strive of developing a reaction sequence for the controlled 

and sequential insertion of distinct organometallics into a PNA oligomer, we have chosen, as a model 

compound, namely, 2-(N-(2-(2-(9H-fluoren-9-yloxy)acetamido)ethyl)pent-4-ynamido)acetic acid 

containing both a PNA backbone and an alkyne side-chain and three different organometallics, 

azidomethyl ferrocene, β-cymantrenoyl-propionic acid and [{N, N-bis((pyridin-2-yl)methyl)prop-2yn-1-amine}Re(CO)3]PF6 

– were inserted using click chemistry, amide bond formation and 

Sonogashira coupling as orthogonal derivatisation methods respectively. Moreover, we discovered, the 

triorganometallic compound (1) has excellent antibacterial activity against a number of multidrug 

resistant gram-positive bacterial strains. 

References 

1. M. Patra, G. Gasser, D. Bobukhov, K. Merz, A.V. Shtemenko, N. Metzler-Nolte, Dalton Trans. 

2010, DOI: 10.1039/c003598j. 

108

P-51 


The Synthesis and Characterization of Aqueous and Organic Soluble, Acid 

Selective Cytotoxic Ruthenium Anticancer Compounds 

Paul J. Dyson, a Olivier Zava, a David J. Kavanagh, b and Andrew D. Phillips* b 

a Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Sciences et Ingénierie Chimiques, 

CH-1015, Lausanne, Switzerland. b University College Dublin, School of Chemistry and Chemical 

Biology, Belfield, Dublin 4 , Ireland.E-mail: andrew.phillips@ucd.ie 

From the serendipitous discovery of cisplatin as an anticancer agent by Rosenberg in 1965, 1 there has 

been considerable interest in the field of metallopharmaceuticals. Currently only two further platinum 

complexes have received worldwide application in cancer treatment, Oxaliplatin and Carboplatin. 

Recently, organometallic ruthenium complexes have attracted greater attention as potential antitumour 

reagents 2-4 and systems featuring oxidation states of +2 and +3 have entered clinical trials. 5 

These Ru compounds (i and ii) are relatively non-toxic in comparison to platinum compounds and the 

mode of inducing apoptosis differs significantly from cisplatin. Therefore, Ru-based pharmaceuticals 

offer valuable alternatives that may overcome Pt resistant tumours and alleviate problematic sideeffects 

observed with other chemotherapeutic drugs. 

This project focuses on the synthesis of water soluble, selective and adaptable ruthenium(II) 

complexes (iii) employing a mixed ligand set that convey a number of useful properties important for 

metallo-pharmaceuticals. The oxygen-stable phosphine, PTA (1,3,5-triaza-7-phosphaadamantane) 

confers water solubility, while the � 5 -coordinated anionic C5H5 group provides the necessary 

lipophilicity for passive cell transport. Uniquely, the bidentate triazapentadienyl ligand allows for the 

‘fine-tuning’ of hydrolysis behaviour by alternating the α-R groups and has proven more stable than 

the related Ru complexes (ii). Moreover, the triazapentadienyl ligand in compound iii imparts 

additional cytotoxicity as observed in previous work on similar � 6 -C6H6 Ru chloro β-diketiminates 

(iv). Finally, we will present our latest research which discusses the further adaption of complexes of 

type iv towards long term biological stability and increased cytotoxicity. 

References 

(i) (ii) (iii) (iv) 

1. B. Rosenberg, L. Van Camp, T. Krigas. Nature. 1965, 205, 698. 

2. P. J. Dyson, A. D. Phillips. Organometallics. 2009, 28, 5061. 

3. B K. Keppler, K. Jakupec. Organometallics. 2008, 27, 2405. 

4. G. Sava, P. J. Dyson,. Int. J. Oncology. 2008, 33, 1281. 

5. (a) C. G. Hartinger, B. K. Keppler, J. Inorg. Biochem. 2006, 100, 891. (b) H. M. Schellens, J. M. 

Rademaker-Lakhai. Clin Cancer Res. 2004, 10, 3717. 

6. A. D. Phillips, O. Zava, R. Scopelitti, A. A. Nazarov, P. J. Dyson. Organometallics. 2010, 29, 417. 

109

P-52 


Encapsulation of Pyrenyl-Containing Dendrimers in 

Arene-Ruthenium Metalla-Prisms 

A. Pitto-Barry, a N. Barry, a R. Deschenaux, a* and B. Therrien a * 

a Université de Neuchâtel, Institut de chimie, 51 Ave de Bellevaux, 2000, Neuchâtel, Switzerland. 

E-mail: bruno.therrien@unine.ch 

Extravasation of macromolecules is considerably enhanced in tumor tissues. This phenomenon called 

“enhanced permeability and retention” (EPR) effect is believed to play a major role in selective 

delivery of nanomedicines. 1 Nanomedicines lead up to 100 times greater intratumor drug delivery 

efficacy to cancer cells as compared to healthy cells. 2 Nanomedicines include antibodies and 

polymeric drug but also large drug delivery vectors like micelles, nanoparticles and dendrimers. 

Among new large drug carriers, we recently proposed to use metalla-prisms built from areneruthenium 

units. 3 These water-soluble and cytotoxic metalla-assemblies offer many possibilities. 

On the other hand, we have been working on dendritic system incorporating lipophilic functionalized 

pyrenes. Encapsulation of the pyrenyl moiety in the hydrophobic cavity of the arene-ruthenium 

metalla-prism, with the dendritic part hanging out of the cage, generates a potential target seeking 

missile for cancer cells. The synthesis and characterization as well as the preliminary cytotoxicity 

studies are presented. 

References 

1. Y. Matsumura, H. Maeda, Cancer Res. 1986, 46, 6387-6392. 

2. H. Maeda, Adv Drug Deliv Rev. 2001, 46, 169-185. 

3. B. Therrien, G. Süss-Fink, P. Govindaswamy, A. K. Renfrew, P. J. Dyson, Angew. Chem. Int. Ed. 

2008, 47, 3773-3776. 

110

P-53 


Silicium dioxide nanoparticles as carriers 

for bio-active organometal complexes 

Gregor Dördelmann a and Ulrich Schatzschneider a * 

a Lehrstuhl für Anorganische Chemie I – Bioanorganische Chemie, Ruhr-Universität Bochum, 

Universitätsstr. 150, D-44801 Bochum, Germany, E-Mail: gregor.doerdelmann@rub.de. 

. 

CO-releasing molecules (CORMs) find steadily increasing use as a stable storage form of carbon 

monoxide for potential therapeutic applications. Several compounds reported, such as 

[Mn(CO)3(tpm-L1)]PF6, show significant cytotoxicity after photoactivation, comparable to that of the 

established anticancer agent 5-fluorouracil (5-FU). [1,2] 

Most solid tumors possess unique pathophysiological characteristics that are not observed in normal 

tissue, like leaky vasculature and impaired lymphatic drainage, leading to an enhanced permeability 

and retention (EPR) of macromolecules in the malignant tissue. [3] Thus, we wanted to explore whether 

silicium dioxide nanoparticles can be utilized as delivery agents for CORMs in solid tumors. 

SiO 2 

N 3 

CuSO 4 5H 2O 

Na-ascorbate 

SiO 2 

+ 

O 

tButOH, H 2O 

N 

N 

N 

O 

N N 

N N 

N N 

N N 

N N 

N N 

Mn CO 

CO 

CO 

Mn CO 

CO 

CO 

Silicium dioxide nanoparticles containing the azidopropyl group were prepared by emulsion 

copolymerization of tetraethylorthosilicate and (3-azidopropyl)triethoxysilane. [4] This procedure 

provides a reproducible synthesis of particles in the ~90 nm size regime as determined by transmission 

electron microscopy (TEM) and dynamic light scattering (DLS). The presence of the azido groups and 

the manganese CORM on the surface of the particles was analysed by spectroscopic methods like 

UV/VIS, IR and NMR spectroscopy as well as energy dispersive X-ray spectroscopy (EDX). 

Reference 

1. J. Niesel, A. Pinto, H.W. Peindy N’Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem. 

Commun. 2008, 1798-1800. 

2. H. Pfeiffer, A. Rojas, J. Niesel and U. Schatzschneider, Dalton Tran . 2009, 4292-4298. 

3. I. Brigger, C. Dubernet, P. Couvreur, Adv. Drug Delivery Rev. 2002, 54, 631-651. 

4. C. A. Bradley, B. D. Yuhas, M. J. McMurdo, T. D. Tilley, Chem. Matter. 2009, 21, 174-185. 

111

P-54 


Synthesis and Biological evaluation of [99mTc]-N-[4-nitro-3-trifluoromethylphenyl] 

Cyclopentadienyltricarbonyltechnetium Carboxamide, a Nonsteroidal 

Antiandrogen Flutamide Derivative 

Tensim Dallagi, a S. Top, b S. Masi, b G. Jaouen, b and M. Saidi a 

a Unité d'utilisation Médicale et Agricole des Techniques Nucléaires Laboratoire des 

Radiopharmaceutiques, Centre National des Sciences et Technologies Nucléaires, 

Technopôle de Sidi Thabet, 2020 Sidi Thabet,Tunisie. E-mail : t.dallegi@laposte.net. b Ecole 

Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel, UMR 7223, 11, rue Pierre et 

Marie Curie, F-75231 Paris Cedex 05, France. E-mail : siden-top@chimie-paristech.fr 

Prostate cancer is one of the most frequently diagnosed cancers and is the second leading cause of 

cancer death in American men, after lung cancer. 1 In 2009, prostate cancer is predicted to kill 27,360 

American men. A similar statistic holds for French men. It is important to note that when the cancer is 

detected it has already had a long time to develop. Therefore, it is crucial to detect the cancer at its 

earliest stages. Few compounds have been labelled with 99m Tc for use as androgen receptor-based 

prostatic imaging agents. 2,3 Rapid metabolic cleavage, low receptor binding affinity or inadequate 

specific activity is a common feature of most of PET and SPECT radioimaging agents. We have 

recently developed ferrocenyl derivatives of nonsteroidal antiandrogens and have found that 

ferrocenyl nilutamide derivatives show a significant cytotoxicity on hormone-independent prostate 

cancer cells PC-3. 4 

O2N O 

O2N O 

F3C N 

H 

F3C N 

Fe 

H 

NFFe 

112 

NF 99m Tc 

NFRe 

99m Tc(CO)3 

(M = 99m Tc) 

(M = Re) 

In our efforts to develop a novel class of SPECT imaging agents based on nonsteroidal androgen 

receptor (AR) antagonists, we have synthesized N-cyclopentadienyltricarbonyltechnetium-N-[4-nitro- 

3-trifluoromethyl-phenyl] carboxamide (NF 99m Tc), an analog of the AR antagonist ligand flutamide. 

NF 99m Tc was obtained in 82% yield from the reaction of N-[4-nitro-3-trifluoromethyl-phenyl]ferrocenecarboxamide 

(NFFe) with fac-[ 99m Tc(H2O)3(CO)3] + in DMF/water at pH 1 and at 150 °C for 

1 h. We also prepared N-[4-nitro-3-trifluoromethyl-phenyl]-rheniumcyclopentadienyltricarbonylcarboxamide 

(NFRe) which is useful for the identification of the technetium compound. In vitro 

assays demonstrated high stability of NF 99m Tc under physiological conditions, buffer and blood. The 

tissue biodistribution in mature male Wistar rats showed a significant selective uptake by prostate but 

this uptake was not blocked by an excess of testosterone acetate. 

References 

1. A. Jemal, R. Siegl, E. Ward, Y. Hao, J. Xu, M. J. Thun, CA Cancer J. Clin. 2009, 59, 225-249. 

2. T. Das, S. Banerjee, G. Samuel, K. Bapat, S. Subramanian, M. R. A. Pillai, M. Venkatesh, Bioorg. 

Med. Chem. Lett., 2006, 16, 5788-5792. 

3 H. He, J. E. Morely, E. Silva-Lopez, B. Bottenus, M. Montajano, G. A. Fugate, B. Twamley, P. D. 

Benny, Bioconjugate Chem. 2009, 20, 78-86. 

4. O. Payen, S. Top, A. Vessières, E. Brulé, M.-A. Plamont, M. J. McGlinchey, H. Müller-Bunz, G. 

Jaouen, J. Med. Chem. 2008, 51, 1791-1799.

P-55 


Synthesis and 99m Tc-Labeling of a PNA Oligomer Containing a New Ligand 

Derivative of 2,2´-Dipicolylamine 

Katrin Jäger, a Gilles Gasser, b Martin Zenker, a Ralf Bergmann, a Jörg Steinbach, a Holger Stephan, a 

and Nils Metzler-Nolte b 

a Forschungszentrum Dresden-Rossendorf, Institute of Radiopharmacy, Bautzner Landstrasse 128, 

01314 Dresden, Germany. b Ruhr-University Bochum, Faculty of Chemistry and Biochemistry, 

Department of Inorganic Chemistry I, Universitätsstrasse 150, 44801 Bochum, Germany. 

E-mail: k.jaeger@fzd.de 

The search for chelating ligands which can be efficiently labeled with radiometals, and which also 

contain a functional group allowing a facile conjugation to biomolecules is currently a hot topic in 

radiopharmacy. The 2,2’-dipicolylamine (Dpa) has already been found to be a good candidate for 

labeling with 186 Re, 188 Re and 99m Tc 1 while the Cu(I)-catalyzed [2+3] azide/alkyne cycloaddition, often 

referred to as Click Chemistry, 2 has been shown to be an effective coupling method. With this in mind, 

we recently developed the facile synthesis of an azido derivative of Dpa (Dpa-N3, Figure 1). 3 

Furthermore, as a proof of principle of the possible functionalization of our ligand to a biomolecule, 

Dpa-N3 was successfully coupled, on the solid phase, to a ethinyl-substituted Peptide Nucleic Acid 

(PNA) oligomer employing the Click Chemistry methodology to give the expected Dpa-ethyl-triazol- 

PNA. Both Dpa-N3 and Dpa-ethyl-triazol-PNA could be efficiently labeled with 99m Tc using the 

precursor [ 99m Tc(H2O)3(CO)3] + to afford [ 99m Tc(CO)3(Dpa-ethyl-triazol-N3)] + and [ 99m Tc(CO)3(Dpaethyl-triazol-PNA], 

respectively. The radionuclide 99m Tc was tightly bound by the Dpa-chelator 

avoiding the formation of pertechnetate for at least 24h. Partitioning experiments in a 1-octanol/water 

system confirmed that both [ 99m Tc(CO)3(Dpa-N3)] + and [ 99m Tc(CO)3(Dpa-ethyl-triazol-PNA] are 

rather hydrophilic. Biodistribution studies of [ 99m Tc(CO)3(Dpa-ethyl-triazol-PNA] in Wistar rats 

showed a fast blood clearance and only a modest accumulation in the kidneys. Similar results were 

found when a mouse model (NMRI nu/nu) was used. 

N 

N 

N 

N 3 

N 

(CO) 99m 

3 Tc 

N 

Figure 1. Structures of Dpa-N3(left) and [ 99m Tc(CO)3(Dpa-N3)] + (right). 

References 

1. T. Storr, C. L. Fisher, Y.Mikata, S. Yano, M. J. Adam, C. Orvig, Dalton Trans., 2005, 654-655. 

2. M. V. Gil, M. J. Arévalo, Ó. López Synthesis, 2007, 11, 1589-1620. 

3. G. Gasser, K. Jäger, M. Zenker, R.Bergmann, J. Steinbach, H. Stephan, N. Metzler-Nolte, 2010, 

submitted. 

113 

N 

N 3 

+

P-56 


Novel MRI Contrast Agents based on a Silsesquioxane Core 

Jörg Henig, a,b* É. Jakab-Tóth, c J. Engelmann, d S. Gottschalk, d H.A. Mayer a 

a Universität Tübingen, Institut für Anorganische Chemie, Auf der Morgenstelle 18, 72076 Tübingen, 

Germany. b Ruhr-Universität Bochum, Zentrum für Elektrochemie, Universitätsstraße 150, 44801 

Bochum, Germany. c CNRS Orléans, Le Centre de Biophysique Moléculaire, 45071 Orléans, France. 

d Max-Planck-Institut für biologische Kybernetik, Hochfeld-Magnetresonanz-Zentrum, 72076 

Tübingen, Germany. E-mail: joerg.henig@rub.de 

Large macromolecular MRI contrast agents (CAs) bearing several paramagnetic gadolinium(III) 

centres show usually significantly higher relaxivities than small size CAs and are particularly useful 

for target specific imaging. However, the large size slows down the excretion rate of the CA, which is 

a major limitation for clinical use. Furthermore, the Solomon-Bloembergen-Morgan theory predicts 

that at the high magnetic fields of modern clinical and especially research MRI scanners, medium-size 

CAs rather than very large systems are the most favored in order to achieve high relaxivities. Here we 

present two novel medium-size CAs (Gadoxane G (GG) and Gadoxane B (GB), Figure 1), based on a 

symmetric T8-silsesquioxane core. The use of the T8-silsesquioxane cube allows the grafting of eight 

monohydrated lanthanide (Ln = Gd 3+ , Y 3+ ) complexes in a confined space. 

Both Gadoxanes can be synthesised with an intact silsesquioxane core. Diffusion 1 H NMR 

measurements showed rotational correlation times of about 3.35 ns for both compounds. Even though 

both CAs have almost identical water exchange rates, due to the lower internal flexibility, the 

longitudinal relaxivities of GB are significantly higher than those of GG over almost the whole range 

of magnetic fields. Although both systems still possess a high internal flexibility, the strong effect of 

the altered spacer on the relaxivity and the comparatively high relaxivity of both systems at proton 

Larmor frequencies above 100 MHz points out the potential of moderate-size silsesquioxane-based 

CAs. Furthermore, with hydrodynamic radii of about 1.44 nm both, GG and GB are still significantly 

smaller than the small pores of the glomerular filtration system and hence should be excreted 

relatively fast via the kidneys. A key feature is also the lability of the silsesquioxane cage under 

physiological conditions (37°C, pH 7.4). No change in relaxivity is observed within the first three 

hours, since the hydrolysis of the initial Si-O-Si moieties has no influence on rotational correlation 

time. However, then the hydrolysis of the silsesquioxane core leads to smaller fragments and therefore 

to a decrease in relaxivity. If needed, this degradation might allow the development of larger CAs, 

whose fragments are then readily excreted via the kidneys. 

R = 

N 

H 

O 

O 

O 

N N 

N 

O O 

Ln 3+ 

Gadoxane G (GG) 

N 

R 

R 

R 

Si 

Si O 

O O 

OO Si R 

Si 

O 

O R 

O 

Si O O 

O 

Si 

R 

R 

Si O Si 

R 

O 

O 

O 

O 

114 

R = 

N 

H 

8- 

O 

O 

O 

N N 

N 

O O 

Ln 3+ 

Gadoxane B (GB) 

Figure 1. Gadoxane G (GG) and Gadoxane B (GB) 

N 

O 

O 

O 

O

P-57 


New Hyperpolazied probes for 13 C-MRI 

S. Aime, a E. Cerutti, a S. Ellena, a R. Gobetto, a F. Reineri, a D. Santelia, a A. Viale a 

a Department of Chemistry I.F.M., University of Torino, Via P. Giuria n° 7, 

10125 Torino, Italy, E-mail: roberto.gobetto@unito.it 

The extraordinary NMR signal enhancement obtained from Para-Hydrogen Induced Polarization 

(PHIP) has been exploited in the investigation hydrogenation mechanisms and, more recently, in the 

development of hyperpolarized contrast agents for MRI applications. In particular the high 

signal/noise ratio that can be achieved on heteronuclei such as 13 C or 15 N allows to obtain molecules 

that can be traced in vivo. In fact the complete absence of those signals in biological tissues leads to 

images in which the background signal derives uniquely from instrumental noise. Furthermore, due to 

long T1 values that can be reached on these nuclei, hyperpolarization can be maintained for enough 

time to allow the acquirement of images in in vivo conditions. 

In order to produce a 13 C hyperpolarized contrast agent using this approach, an unsaturated substrate is 

necessary (usually a triple bond containing molecule, that is efficiently para-hydrogenated in the 

presence of a suitable catalyst), with an adjacent carbonyl group to which hyperpolarization is 

transferred due to its coupling with parahydrogen protons. This group is also characterized by a long 

T1 value (which limits the polarization loss due to relaxation). 2 Then, in order to use heteronuclear- 

PHIP for MRI application, longitudinal hyperpolarization must be obtained from spin order which 

derives directly from parahydrogenation. This task can be achieved by means of both field cycling 

procedure or an appropriate pulse sequence. 

We present the synthesis and parahydrogenation experiments of a series of novel substrates with the 

aim of obtaining an in-depth understanding of the potential of these species as 13 C hyperpolarized 

contrast agents. Particular attention is focused on bio-compatible and water soluble parahydrogenated 

products. Problems concerning catalyst and organic solvent elimination have been also tackled. 

References 

1) K. Golman, O. Axelsson, H. Johannesson, S. Mansson, C. Olofsson, J.S. Petersson, Magn. Res. 

Med. 2001, 46, 1. 

2) F. Reineri, A. Viale, G. Giovenzana, D. Santelia, W. Dastrù, R. Gobetto, S. Aime, J. Am. Chem. 

Soc. 2008, 130, 15047. 

115

P-58 


Affinity Binding for Controlled Orientation and Electrochemistry in Self 

Assembled Monolayers of Reductases. 

Nicolas Plumeré, a Ellen R. Campbell, b Bill H. Campbell b 

a Ruhr Universität Bochum, Center for Electrochemical Science, Universitätsstrasse 150, 44780, 

Bochum, Germany. b NECi, 334 Hecla Street, Lake Linden, USA. E-mail: nicolas.plumere@rub.de 

Metal-chelating ligands have been designed in the field of immobilized metal ion affinity 

chromatography 1 (IMAC) for the purification of polyhistidine-tagged (His-tagged) proteins. Dense 

monolayers of similar metal-chelating ligands on electrode surfaces have recently been applied for the 

immobilization and controlled orientation of His-tagged proteins via affinity binding. 2–4 In particular, 

nitrilotriacetic (NTA) and imminodiacetic (IDA) acid terminated gold and carbon electrodes were used 

for the immobilization of laccase, 4 glucose oxidase, 5 horseradisch peroxidase 2 and hemoprotein. 3 In 

these cases, the attachment of the enzyme via His-tag yields fully active protein films in the presence 

of electron mediators. In some cases, direct electron transfer was observed as well. 5 Cu 2+ and Ni 2+ 

were used as the metal cations. 

However, the use of affinity binding involving Ni 2+ or Cu 2+ is limited to applications that require redox 

potentials less negative than the reduction potential of the metal cation complexes. 2 Therefore, most 

reductases cannot be used in such systems. 

In order to overcome this limitation, we used Zn 2+ as the metal cation for the coordination of a Histagged 

reductase. Nitrate reductase (NaR) as the enzyme and methyl viologen as the electron mediator 

were chosen to test the affinity binding via Zn 2+ cations on NTA modified glassy carbon electrodes. 

The electrochemical investigations of the NaR monolayer on NTA-Zn 2+ films demonstrate the activity 

for the catalytic reduction of nitrate to nitrite in presence of methyl viologen. The catalytic current 

density corresponds to the one expected for a fully active enzyme monolayer. Moreover, the reduction 

of the Zn 2+ is not observed at the potential necessary for the reduction of methyl viologen. Therefore, 

affinity binding based on Zn 2+ may be used for the immobilization of Nitrate reductases in their active 

form. 

References 

1. G. S. Chaga J. Biochem. Biophys. Methods 2001, 49, 313-334. 

2. R. Blankespoor, B. Limoges, B. Schöllhorn, J.-L. Syssa-Magalé, D. Yazidi Langmuir 2005, 21, 

3362-3375. 

3. V. Balland, S. Lecomte, B. Limoges Langmuir 2009, 25, 6532-6542. 

4. V. Balland, C. Hureau, A. M. Cusano, Y. Liu, T. Tron, B. Limoges Chem. Eur. J. 2008, 14, 7186- 

7192. 

5. S. Demin, E. A. H. Hall, Bioelectrochemistry 2009, 76, 19-27. 

116

P-59 


Synthesis, Characterization and Properties of the Cluster Rhenium(ІІІ) 

Compound with β-Alanine Ligands 

Mariia S. Randarevych, a Kateryna A. Zablotska, a Konstantin V. Domasevitch, b Alexander V. 

Shtemenko a 

a Department of Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin 

Ave. 8, Dnipropetrovs’k 49005, Ukraine. E-mail: shtemenko@ukr.net. b Department of Inorganic 

Chemistry, Kiev University, Volodimirska Street 64, Kiev 01033, Ukraine. E-mail: dk@univ.kiev.ua. 

The theoretical interest in binuclear complex compounds of dirhenium(ІІІ) is caused by the fact that 

rhenium is one of the few elements that are able to form a multiplet metal-metal bond. From the 

practical point of view, these compounds can be used in medical practice since they have 

anticancerogenic, antihemolytic, and antiradical properties and lower toxicity in comparison with 

other well-known compounds of transition metals. 

One of the received cluster compounds of dirhenium(ІІІ) with γ-aminobutyric acid’s ligands has 

already shown excellent antitumor properties. 1 Owing to this, our purpose is to expand the range of 

similar compounds by using other amino acids as ligands which possess own biological activity. 

Therefore, the synthesis of new cluster aminocarboxylates of dirhenium(III) and the study of their 

physicochemical and biological properties are of great interest for us. A synthetic procedure of 

dirhenium(ІІІ) complex compound with β-alanine was developed. The properties of this compound are 

investigated by spectral method. The compound cis-Re2Cl6{�-AlaH}2 ·1.5H2O is shown to consist of 

coordinating centre Re2 6 + with quadruple bond rhenium-rhenium. In equatorial positions there are 

bridge groups containing β-alanine residues being in cys-position relative to Re-Re. The structure of 

the given compound is presented on fig. 1. 

Fig.1 cis-Re2Cl6{�-AlaH}2 ·1.5H2O 

The structure of this compound is confirmed by direct X-ray structure, thermal and spectral analyses. 

We have also investigated the biological activity of the complex that revealed itself perspective as a 

cytostatic and anticancer agent. 

References 

1. A. Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, E. Zabitskaya, A. Golichenko Dalton 

Trans. 2009, 26, 5132 - 5136. 

117

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Exploring Histidines as Biomolecular Anchors to Re(CO)3 + 

Richard S. Herrick, a Christopher J. Ziegler, b Roger Rowlett, Americo Gambella a 

a College of the Holy Cross, Department of Chemistry, 1 College St., Worcester, MA 01610, USA. 

b University of Akron, Department of Chemistry, KNCL 402, Akron, OH 444325, USA. c Department 

of Chemistry, Colgate University, 13 Oak Drive, Hamilton, NY 13346 (USA). 

E-mail: rherrick@holycross.edu 

In recent years we have explored the potential of using amino acids and amino acid conjugates to bind 

Re(CO)3 + . We are currently exploring the use of histidine-containing peptide conjugates as models of 

His-tags in order to test their ability to bind the Re(CO)3 + . His-OMe, Ac-His-OH and His-His-OH 

were each exposed to aqueous solution of Re(CO)3 + . Reaction with His-OMe lead to ester cleavage 

and formation of the previously observed Re(CO)3(� 3 -N�,N�,O - -His). Reactions with Ac-His-OH and 

His-His-OH each led to novel compounds containing a carboxamido N-donor group. The 

characterization, including X-ray crystallography, of each compound, and testing of each compounds 

ability to withstand challenge experiments will be discussed. 

We have also been interested in using proteins to bind Re(CO)3 + . Little work has been carried out on 

reactions between rhenium prodrug or drug model complexes and proteins. Such interactions can be 

crucial to the biological processing of Tc/Re based imaging agents, since proteins, rather than 

nucleotides or single amino acids, would be encountered in plasma. Alternatively, protein-Tc/Re 

adducts could be novel targets for use as imaging or therapeutic agents. In order to probe this 

chemistry, we are examining the interactions between Re(CO)3(H2O)3 + and the readily crystallizable 

protein lysozyme. A crystal structure has been obtained of a lysozyme-Re(CO)3(H2O)2 adduct. 

Experimental details, including the new crystal structure, will be discussed. 

From these studies highlighting the binding of histidines in peptides and proteins to Re(CO)3(H2O)3 + , 

several conclusions can be drawn. These will be discussed along with future directions of this 

research. 

118

P-61 


Fluorescent Rhenium(I)tricarbonyl Complexes Based on a Novel 

Bisphenanthridinyl Chelate 

Lukasz Raszeja, a and Nils Metzler-Nolte *a 



E-mail: LukaszRaszeja@aol.com 

Fluorescence microscopy is a powerful technique for the imaging of biological systems. Beside 

making endogenous cell organelles visible by specific staining methods, it is also possible to monitor 

the intracellular distribution of fluorescently labelled compounds such as peptides, oligonucleotides or 

drugs in general. Right now most of the fluorescent dyes used for labelling are organic compounds 

based on an aromatic heterocycle like in the case of fluorescein, acridine or cyanine. By now, the 

number of applications of d 6 metal complexes for cellular imaging experiments is modest. Published 

systems use the typical luminescent Ir(III), Ru(II) and Re(I) metal complexes. 1 

We have developed a novel chelating ligand system based on phenanthridine. This ligand is 

fluorescent itself, but by complexing a fac-Rhenium(I)tricarbonyl core the molecule exhibits an 

enhanced absorption and a stronger and red shifted fluorescence. With a typical broad absorption 

maximum between 310 nm and 380 nm the complex shows strong emission at 540 nm by excitation at 

350 nm. The large Stokes shift is a big advantage in comparison to the typical organic dyes due to 

prevent self-quenching processes. Beside the application in fluorescence microscopy our ligand could 

act as a potential radio marker in the case of complexing the isostructural { 99m Tc(CO)3} core. 

Several compounds based on the Bisphenanthridine moiety were synthesized (example in Fig. 1), fully 

characterized and finally used for cellular imaging and uptake experiments (Fig. 2). The synthesis of 

bioconjugates of peptides and PNA was also successful and cellular uptake studies show interesting 

and promising results. 

References 

O 

O 

N 

N 

N 

I 

Re 

CO 

CO 

CO 

Br 

Fig. 1 Structure of the fluorescent Re I complex 1. Fig. 2 Fluorescence image of IMIM-PC2 cells after 

incubation with 1 (5 µM, 24 h). 

1. V. Fernández-Moreira, F. L. Thorp-Greenwood, M. P. Coogan, Chem. Commun. 2010, 46, 186-202. 

119

P-62 


Electrochemical Detection of Protein Kinases and Inhibitor Screening by Using 

Ferrocene-ATP Bioconjugate 

Sanela Martić, Mahmoud Labib and Heinz-Bernhard Kraatz* 

The University of Western Ontario, Faculty of Science, Department of Chemistry, 1151 Richmond 

Street, N6A 5B7, London, Canada. 

E-mail: smartic@uwo.ca 

Protein kinase plays a critical role in the cellular growth, signalling and function and its malfunction 

has been linked to a number of diseases, such as cancer. 1 For diagnostic and drug screening purposes 

detecting, monitoring and quantifying kinase activity is critical. Recently, an electrochemical 

biosensor was developed and was used in our laboratory for measuring casein kinase 2 (CK2) and 

protein kinase C (PKC) activity on a Au surface by means of the electroactive adenosine-5’-[γferrocene] 

triphosphate conjugate (Fc-C6-ATP), as a co-substrate for the protein kinase. 2 As an 

extension of this work, we have investigated following kinases: sarcoma-related kinase (Src), cyclindependent 

kinase (CDK2) and extracellular signal–regulated kinase (Erk1), all of which are directly 

involved in the cell cycle. The electrochemical detection of kinase activity and drug target screening 

was performed in addition to the surface characterization of phosphorylated assays by MALDI-TOF 

MS, XPS and TOF-SIMS techniques. A proof-of-concept study was performed using the newly 

developed multiplex chip technology which allows for monitoring and quantifying multiple kinase 

activities for the first time. The optimized electrochemical multiplex assay was also used for 

identification of novel protein kinase inhibitors. 

References 

Erk1 

CDK2 

control 

Src 

120 

Fe 

O 

N 

H 

PO 3 Fc 

6 

N 

H 

ATP 

No electrochemical signal ! 

Electrochemical signal 

after phosphorylation! 

1. (a) G. Manning, D. B. Whyte, R. Martinez, T. Hunter, S. Sudarsanam, Science, 2002, 298, 1912- 

1934. (b) J. S. Sebolt-Leopold, J. M. English, Nature, 2006, 441, 457-462. 

2. (a) H. Song, K. Kerman, H. B. Kraatz, Chem. Commun. 2008, 502-504. (b) K. Kerman, H. Song, J. 

D. Duncan, D. W. Litchfield, H. B. Kraatz, Anal. Chem. 2008, 80, 9395-9401.

P-63 


Electrochemical Evaluation of the Interaction between Ru(II) mono-diimine 

Complexes and Biomolecules 

Mauro Ravera, a Ayesha Sharmin, b Edward Rosenberg, b Domenico Osella, a 


Viale Michel 11, 15121, Alessandria, Italy. b Department of Chemistry and Bio-Chemistry, University 

of Montana, Missoula, MT 59812, USA. E-mail: mauro.ravera@mfn.unipmn.it 

Transition metal luminescent complexes containing one or more diimine ligands typically have 

excited-state lifetimes ranging from about 100 ns to 10 �s. Because the lifetimes of these 

luminophores are long compared to fluorescent dyes that are used as biological probes, time-gated 

detection can be used to suppress interfering auto-fluorescence from the biological sample. In 

addition, highly polarized emission from some of these complexes has stimulated interest in using 

them as biophysical probes for studying the dynamics of macromolecular assemblies and interactions 

on membranes. 

The series of complexes [XRu(CO)(L–L)(L’)2][PF6] (X = H, TFA, Cl; L–L = 2,2’-bipyridyl, 1,10phenanthroline, 

5-amino-1,1’-phenanthroline and 4,4’-dicarboxylic-2,2’-bipyridyl; L’2 = 2PPh3, 

Ph2PC2H4PPh2, Ph2PCH=CHPPh2) have been synthesized from the starting complex 

K[Ru(CO)3(TFA)3] (TFA = CF3CO2). The purpose of the project was to synthesize a series of 

complexes that exhibit a range of excited-state lifetimes and that have large Stokes shifts, high 

quantum yields and high intrinsic polarizations associated with their metal-to-ligand charge-transfer 

(MLCT) emissions. To a large degree these goals have been realized in that excited-state lifetimes in 

the range of 100 ns to over 1 �s are observed. 1 

The measured quantum yields and intrinsic anisotropies 

are higher than for previously reported Ru(II) complexes. Interestingly, the neutral complex with one 

phosphine ligand shows no MLCT emission. The compounds show multiple reduction potentials 

which are chemically and electrochemically reversible in a few cases as examined by cyclic 

voltammetry. The same technique has been use to evaluate the interaction between some of the 

synthesized complexes and biomolecules (DNA and bovine serum albumin, BSA). 

SWV of a solution of 1 with successive additions of BSA. Electrochemical conditions: 0.5 mM of 

complex in 0.05 M phosphate buffer (pH 7.4) + 5% DMSO; glassy carbon electrode 

References 

1. A. Sharmin, R. C. Darlington, K. I. Hardcastle, M. Ravera, E. Rosenberg, J. B. A. Ross, J. 

Organomet. Chem., 2009, 694, 988-1000. 

121

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Electrochemical Studies of Fc-PNA(•DNA) Surface Dynamics 

Nina Hüsken, a Magdalena Gębala, b Wolfgang Schuhmann b and Nils Metzler-Nolte *a 

a Ruhr-Universität Bochum, Fakultät für Chemie und Biochemie, Lehrstuhl für Bioanorganische 

Chemie, Universitätsstrasse 150, 44801 Bochum, Germany. b Ruhr-Universität Bochum, Fakultät für 

Chemie und Biochemie, Analytische Chemie, Universitätsstrasse 150, 44801 Bochum, Germany. Email: 

nina.huesken@rub.de 

The application of peptide nucleic acids (PNA) as receptor molecules in DNA biosensors promises an 

enhanced specificity and selectivity for the analysis of DNA, due to the favourable hybridization 

properties of PNA. N-terminal ferrocene (Fc) labelled and C-terminal gold surface confined PNA 

oligomers present unique tools for electrochemical DNA biosensing, since structural and 

conformational changes of the nucleic acid strand directly affect the Fc-electrode redox process. 1 

By means of fast scan cyclic voltammetry (FSCV), the kinetic of the Fc-electrode redox process was 

studied at Fc-PNA(•DNA) modified gold electrodes. The gold surfaces were loosely packed (< 8%) 

with Fc-PNA(•DNA) single or double strands, to exclude any lateral interactions between the probe 

molecules and to facilitate with this an unrestricted thermal strand motion of the Fc tethered strands. 

These studies primary revealed, that the large elasticity of the PNA single strand evokes a diffusion 

like motion of the Fc head group (“Fc-on-rope”), whereas the Fc label attached to the rather rigid 

PNA(•DNA) duplex exhibits a significantly less diffusional behaviour (“Fc-on-rod”). Based on the 

FSCV studies, a clear correlation between the determined electron transfer (ET) rate constants k 0 and 

the inherent strand elasticity was developed. Thereby a large strand elasticity leads at high scan rates 

to a ‘kinetic freeze’ of the tethered Fc head groups, to result in a large spectrum of Fc-electrode 

distances and a large average Fc-electrode distance, being correlated to a rather low ET rate constant. 

Vice versa, an increase in the strand rigidity leads to a smaller spectrum of possible Fc-electrode 

distances and an average Fc-electrode distance, which is located closer to the gold surface due to an 

attractive effect exerted by the electric field and hence correlates a larger ET rate constant. 2 

Concluding, the established correlation between the Fc-electrode ET rate constants, determined by 

FSCV, and the inherent PNA(•DNA) strand elasticity renders the ET rate constants a new means to 

study Fc-PNA(•DNA) surface dynamics. This correlation furthermore presents the basis for an 

electrokinetic analysis of DNA with Fc-PNA biosensors. 

References 

1. N. Hüsken, M. Gębala, W. Schuhmann, N. Metzler-Nolte, ChemBioChem 2010, DOI: 

10.1002/cbic.200900748 

2. N. Hüsken, M. Gębala, W. Schuhmann, N. Metzler-Nolte, manuscript submitted. 

122

P-65 


Study of Heavy Metals Biosorption from Aqueous Solutions 

by Using Biological Wastes 

Mohammad Ali Zazouli, *a and Mayram Bagheri a 

a Department of Environmental Health Engineering, Faculty of Health, Mazandaran University of 

Medical Sciences, Sari, Iran, E-mail: Zazoli49@yahoo.com 

Heavy metal pollution is posing significant threats to the environment and public health because of its 

toxicity, non-biodegradability and bioaccumulation. 1 The increasing environmental concern for these 

contaminants, there has been serious interest in removal of heavy metals from contaminated 

wastewater & water. A number of technologies such as precipitations, ion exchange, membrane 

processes and adsorption on activated carbon, have been used over the years to remove toxic metals 

from water but these techniques are often ineffective and/or very expensive in the reduction of heavy 

metals from water at very low concentration. 2 The search for alternative and innovate treatment 

techniques has focused attention on the use of biological materials for heavy metal removal. The 

objective of this study is to investigate of heavy metals (Cadmium, Chromium and lead) biosorption 

from aqueous solutions by using orange mesocarp and rice husk. 

The selected biomass were first cut into small size, washed with water to remove impurity and soluble 

components and oven-dried at 100 o C for 24h until constant weight was reached. The washed and 

dried materials were crushed and sieved using 1.00 mm mesh size sieve. Then pretreated separately 

with soaking in NaOH(0.4N) and HNO3(0.4N) for 24h. After that washed with distilled water until it 

had no color in the filtrate. Biosorption studies were carried out batch method. After the desired 

contact time, the biosorbent was removed by filtration. The metal concentrations were measured by 

using atomic absorption spectrophotometer. All experiments were conducted in duplicate. Finally, 

Adsorption isotherms of metal on adsorbents were determined. 

Results show that metal sorption initially increases with increasing in metal concentration in the 

solution, and then becoming saturated after a certain concentration of metal. The maximum sorption 

capacities with orange waste were for Cr and with rice husk was Pb. The results showed that the 

percentage removal of metals as a function of equilibrium pH. The effect of pH on metals sorption was 

very different for all metals and for two biosorbents. Biosorption was very fast for the first 30 min but 

slowed markedly after 1 h. Biosorption continued to increase after which it became constant reaching 

equilibrium. The adsorption data fit well with the Langmuir and Freundlich isotherm model for orange 

waste and rice husk, respectively. 

This study indicates that both biomass residues have the capacity to remove metal ions from aqueous 

solution, and the amount of the heavy metal ions bound by cellulosic substrate depends on the metal 

ion type, biosorbent type and dosage, pH and contact time. Thus, orange waste and rice husk could be 

potentially used for the removal of heavy metals from aqueous solution as erials stand out as very 

good and lowest biosorbents. 

Keywords: Biosorption, Heavy metals, Orange wastes, Rice husk, Biological wastes 

References 

1. E.-S. Z. El-Ashtoukhy, N.K. Amin, O. Abdelwahab, Desalination. 2008, 223, 162-173. 

2. A.B. Pérez-Marín, A. Ballester, F. González, M.L. Blázquez, J.A. Muñoz, J. Sáez, V. Meseguer 

Zapata, Bioresour. Technol. 2008, 99, 8101-8106. 

123

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Synthetic Analogs for Evaluating Organometallic and Nickel(0) Involvement in 

Acetyl Coenzyme A Synthase 

Molly J. O’Hagan, Nathan A. Eckert, and Charles G. Riordan *a 

a University of Delaware, Department of Chemistry and Biochemistry, 19716, Newark, USA. 

E-mail: riordan@udel.edu 

Acetyl coenzyme A synthase (ACS) is a NiFeS protein found in archaea and anaerobic organisms that 

can grow on CO2 as their sole carbon source. 1 Some of these, including methane, acetate and sulfateproducing 

organisms are found in the intestinal tracts of higher mammals including humans. ACS 

catalyzes the dis/assembly of a methylcorrinoid, CO and CoA to acetyl CoA. The mechanism of the 

reaction undoubtedly involves bioorganometallic intermediates, although none have yet to be directly 

identified. Using small molecule synthetic chemistry, we seek to establish chemical precedents for 

relevant, elementary steps in ACS catalysis. 2 Central among these is the transalkylation of 

methylcorrinoid to a reduced site of the ACS cluster. One proposal for this site is a zero-valent nickel 

ion. 3 Studies detailed in this presentation establish the feasibility and mechanistic boundaries for alkyl 

group transfer to nickel(0) and nickel(I) acceptors with emphasis on our recent results in deducing the 

mechanism of a model in which SN2 transfer to nickel(0) is suggested. 4 

References 

1. S.W. Ragsdale, E. Pierce, Biochim. Biophys. Acta 2008, 1784, 1873-1898. 

2. (a) R. Krishnan, J.K. Voo, C.G. Riordan, L. Zakharov, A.L. Rheingold, J. Am. Chem. Soc. 2003, 

125, 4422-4423; (b) R. Krishnan, C.G. Riordan, J. Am. Chem. Soc. 2004, 126, 4484-4485. 

3. P.A. Lindahl, J. Biol. Inorg. Chem. 2004, 9, 516-524. 

4. N.A. Eckert, W.G. Dougherty, G.P.A. Yap, C.G. Riordan, J. Am. Chem. Soc. 2007, 129, 9286- 

9287. 

124

P-67 


Synthesis of Mixed Gold(I)-Phosphine-Ferrocene-Phenylalanine 

and Peptide Conjugates 

Christine Doffek, a S. David Köster, a and Nils Metzler-Nolte *a 

a Ruhr-Universität Bochum, Lehrstuhl für Anorganische Chemie I, Universitätsstraße 150, 

D-44801 Bochum, Germany. E-mail: christine.doffek@rub.de 

The combination of gold(I)-phosphine and ferrocene derivatives enlarges the number of interesting 

bioconjugates. The gold(I)-phosphine-ferrocene-phenylalanine conjugate 1 was prepared by Cu(I)catalyzed 

[3+2]-cycloaddition of azido-modified phenylalaninemethylester with the internal alkyne of 

a gold(I)-phosphine-ferrocene-acetylide in good yields. 1,2 The corresponding peptide conjugate was 

synthesized using solid phase peptide synthesis (SPPS) in combination with Cu(I)-catalyzed [3+2]cycloaddition 

of the azido-modified peptide with the gold(I)-phosphine-ferrocene-acetylide, also 

showing good yields. During the final cleavage the peptide conjugate decomposed. The gold(I)phosphine-ferrocene-phenylalanine 

conjugate 1 was comprehensively characterized by multinuclear 

and multidimensional NMR spectroscopy, mass spectrometry and cyclic voltammetry (CV). The 

electrochemical studies showed reversible processes of the redox couple Fc 0 /Fc + (Fc = ferrocenyl) and 

an irreversible reduction of Au + to Au 0 . 

References 

O 

O 

O 

125 

1 

Au 

N 

N 

N 

1. D. A. Gray, L. Gao, T. S. Teets, J. B. Updegraff III, N. Deligonul, T. G. Gray, Organometallics 

2009, 28, 6171-6182. 

2. S. Back, R. A.. Gossage, H. Lang, G. van Koten, Eur. J. Inorg. Chem. 2000, 1457-1464. 

Fe

P-68 


Study of Interaction of Gold Drugs with Thiols 

Using Various Analytical Techniques 

Gohar T. Kazimi a* and Mohammad S Iqbal b 

a Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan. E-mail: 

gohartaqi@hotmail.com 

b Department of Chemistry, GC University, Lahore 54000, Pakistan. E-mail: saeediq50@hotmail.com 

Since ancient times, gold has occupied a special place in medicine to cure diseases. Now a days gold 

based drugs are being used in the treatment of an autoimmune inflammatory disease known as 

rheumatoid arthritis (RA). 1 Solganal TM (gold thioglucose), Myochrisine TM (gold sodium thiomalate) 

and Ridaura TM (auranofin, 2,3,4,6-tetraacetyl-β-1-D-thiogluco-pyranosato-S-(triethyl phosphine)gold(I), 

Et3PAuStagl) are used for the treatment of this disease but their mode of action is still 

uncertain. Furthermore, several studies have demonstrated that several gold (I) and gold (III) salts also 

exhibit anti-tumour activities. 2-4 The pharmacokinetic and pharmacological properties of these drugs 

mainly depend upon ligands present on them and various studies have shown that these ligands are 

replaced in the body by some endogenous molecules. 1 

In this work some of the ligand exchange reactions of gold drugs with various thiols including 

cysteine, glutathione, N-acetylcysteine and O-methylcysteine were studied in both solution and in 

solid state. Various analytical techniques like ESI-MS, DESI-MS, pXRD and FT-IR used in this study 

confirmed the ligand exchange mechanism. ESI-MS was successfully employed for characterization of 

the ligand-exchange products. When cysteine reacts with auranofin in solution, the formation of 

[Et3PAuSCy] – (m/z = 434), [taglSAuCyS] – (m/z = 680) and [Au(Stagl)2] – (m/z = 923) were observed 

along with [Au(PEt3)2] + (m/z =433) in the positive-ion spectrum. Similarly with O-methylcysteine the 

formation of [TaglSSOMeCy] – (m/z = 497), [taglSAuSOMeCyS] – (m/z = 694), [Au(Stagl)2] – (m/z = 

923) and [Et3PAuSOMeCy] + (m/z =450) indicated the ligand exchange during reaction. DESI-MS, 

pXRD and FT-IR were found to be helpful in characterization the products of the reactions performed 

in the solid state. 

This study provides very useful information in understanding the in vivo biochemistry of the gold 

drugs used for rheumatoid arthritis. 

References 

1. C.F. Shaw, III, Chem. Rev. 1999, 99, 2589-2600. 

2. E.R.T. Tiekink, P.D. Cookson, B.M. Linahan, L.K. Webster, Metal-Based Drugs 1994, 1,299. 

3. L.K.Webster, S. Rainone, E. Horn, E.R.T. Tiekink, Metal-Based Drugs 1996, 3, 63. 

4. D. Crump, G. Siasios, E.R.T. Tiekink, Metal-Based Drugs 1999, 6, 361. 

126

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Glutathione Reductase/Thioredoxin Reductase Systems as Molecular Target for 

Antiproliferative Gold(I) Carbene Complexes 

R. Rubbiani a and I. Ott *a 

a Institute of Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 

38106 Braunschweig, Germany, r.rubbiani@tu-bs.de 

Human Thioredoxin-Reductase (TrxR) and Glutathione-Reductase (GR) are two NADPH-dependent 

flavoenzymes belonging to the main responsibles of the antioxidant cellular network. They consist of a 

FAD domain, a NADPH domain but they differ for the active site, which is characterized by a 

cysteine-cysteine (Cyscys) bridge in the case of GR and by a cysteine-selenocysteine (Secys) bridge in 

the case of TrxR. The main substrate of GR is glutathione (Glu), a tripeptide formed by γ-L-Glutamyl- 

L-cysteinylglycine that has the role to act directly against reactive oxygen species (ROS). The 

substrate of TrxR is thioredoxin (Trx), a protein of 12 kDa with an active disulfide motif. 1 With the 

development of Auronafin, it has been demonstrated that certain metal complexes (especially gold 

complexes) have a strong affinity for TrxR, based on the formation of a covalent bond. 2 Because of the 

overexpression of these enzymes in the tumoral cells, as well as their substrates, they become a 

possible target for the developing of new active molecules. Based on a computational study, our 

research focuses on gold(I) carbene complexes, a new stable class of compounds that show activity on 

these enzymatic systems. We synthesized a series of di-substituted benzimidazole carbenes (see 

figure) and evaluated their interactions with the mentioned substrates and enzymes. We also 

investigated the proliferation inhibition in two tumoral cell lines. Our results indicate a selective 

inhibition of TrxR in the nanomolar range, most probably due to the stronger affinity of gold(I) for 

Secys compared to Cys. The proliferation studies showed a cytotoxic activity in the range of 7-16 µM. 

References 

1. S. Gromer et al., Med. Res. Rev. 2004, 24, 40-89. 

2. I. Ott.,Coord. Chem. Rev. 2009, 52, 763-770. 

127

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Synthesis, Characterization and Antitumor Screening of some 

Di- and Triorganotin(IV) Complexes of 2,9-Dimethyl-1,10-phenanthrolin 

Mojdeh Safari,* a Mohammad Yousefi, a Maryam Bikhof, a Amir Amanzadeh, b 

Mohammad Ali Shokrgozar, b and Fatemeh Tavakolinia a 

a Azad University, Shahre-rey branch, Tehran, Iran 

b Pasteur Institute, Tehran, Iran. E-mail: msafari96@yahoo.com 

Malignancy is the result from a multiple process by accumulation of mutations and other genetic 

alteration. 1 Searches for non-platin metal-based antitumor drugs have attracted considerate interest. 

Diorganotin(IV) complexes are potential antitumor agents mainly active against P388 lymphocytic 

leukemia and other tumors. 2-4 Recent studies have shown very promising in vitro antitumor properties 

of organotin compounds against a wide panel of tumor cell lines of human origin. 5-11 In some cases, 

organotin(IV) derivatives have also shown acceptable antiproliferative in vivo activity as new 

chemotherapy agents. 12-17 In this context ,we decided to study the cytotoxic activity of 2,9-Dimethyl- 

1,10phenanthrolin tin(IV) derivatives, in order to observe the influence of the substituents attached to 

the central Sn atom on the final anticancer activity of the organotin(IV) complexes. In the present 

research the new complexes of organotin were obtained by reacting R2SnCl2 and Ŕ3SnCl (where R= 

Methyl, Butyl, Benzyl and Ŕ= Phenyl) with 2,9-Dimethyl-1,10phenanthrolin. These complexes have 

been characterized by FT-IR and 1 H, 13 C, 119 Sn NMR and Mass spectroscopy. The cytotoxic activity of 

the studied compounds has been investigated against K562 cell line and the IC50 values have been 

determined. 

References 

1. P. Blume-Jensen, T. Hunter, Nature, 2001, 411, 355–357. 

2. A.J. Crowe: Antitumor activity of tin compounds in Metal Compounds in Cancer Therapy; S.P. 

Fricker, Ed., Chapman & Hall: London, GB, 1994, pp. 147–179. 

3. A.J. Crowe, P.J. Smith, C.J. Cardin, H.E. Parge, F.E. Smith, Cancer Lett., 1984, 24, 45–48. 

4. (a) A.K. Saxena, F. Huber, Coord. Chem. Rev., 1989, 95, 109–123. (b) M. Gielen (Ed.), Tin-Based 

Anti-Tumor Drugs, Springer-Verlag, Berlin, 1990. 

5. M. Gielen (Ed.), Tin-Based Anti-Tumor Drugs, Springer-Verlag, Berlin, 1990. 

6. M. Gielen, Coord. Chem. Rev., 1996, 151, 41-51. 

7. P. Yang, M. Guo, Coord. Chem. Rev., 1999, 189, 185–186. 

8. M. Gielen, M. Biesemans, D. De Vos, R. Willem, J. Inorg. Biochem., 2000, 79, 139-145. 

9. M. Gielen, Appl. Organomet. Chem., 2002, 16, 481-494. 

10. S.K. Hadjikakou, N. Hadjiliadis, Coord. Chem. Rev., 2009, 253, 235-249. 

11. in Tin Chemistry: Fundamentals,Frontiers, and Applications; M. Gielen, A.G. Davies, K. Pannell, 

E. Tiekink, Ed.: John Wiley and Sons, Wiltshire, 2008. 

12. L. Nagy, A. Szorcsik, K. Kovacs, Pharm. Hungarica, 2000, 70, 53-71. 

13. M. Nath, S. Pokharia, R. Yadav, Coord. Chem. Rev., 2001, 215, 99-149. 

14. M. Gielen, in: NATO ASI Ser. 2, vol. 26, 1997, p. 445. 

15. D. De Vos, R. Willem, M. Gielen, K.E. Van Wingerden, K. Nooter, Met. Based Drugs, 1998, 5, 

179-188. 

16. C. Pettinari, Main Group Met. Chem., 1999, 22, 661-692. 

17. S.P. Fricker, Ed., Metal Compounds in Cancer Therapy, Chapman & Hall, London, UK, 1994, pp. 

147–179. 

128

P-71 


Synthesis of Chromium-Containing Diterpene Analogs 

for the Modulation of NOD Proteins 

Aroonchai Saiai a , Janna Velder a , Harald Bielig b , Tomas A. Kufer b , Hans-Günther Schmalz* a 

a Institute for Organic Chemistry, University of Cologne, Greinstr.4, 50939, Cologne, Germany. 

b Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Joseph- 

Stelzmann-Str.9, Geb.37, 50931, Cologne, Germany. E-mail: asaiai@smail.uni-koeln.de 

Polymorphisms in NOD1 and NOD2 are linked to chronic inflammatory barrier diseases such as 

asthma, Blau syndrome, early onset sarcodoisis and Crohn’s disease. 1 Many synthetic compounds in 

our group are structurally related pseudoterosins which exhibit pronounced analgesic and antiinflammatory 

properties were screened. In continuative research, we found that AKS-01 can inhibit 

NOD2-mediated NF-KB activation. 

To investigate the structure-activity relationships, Cr(CO)3-complexed compounds which structurally 

related to AKS-01were synthesized. 2,3 

Synthesis and biological evaluation will be presented in details. 

References 

OMe 

H 

OMe 

Cr(CO) 3 

H 

N 

AKS-01 

OMe 

Cr(CO) 3 

1.(a) P. Hysi, M. Kabesch, M. F. Moffatt, M. Schedel, D. Carr, N. Klopp, A.W. Musk, A. James, G. 

Nunez, N. Inohara and W.O. Cookson, Hum mol genet. 2005, 14, 935-941; (b) P. Rosenstiel, A. Till 

and S. Schreiber, Microbes and infection. 2007, 9, 648-657. 

2. H.-G. Schmalz, S. Siegel and J.W. Bats, Angew. Chem. Int. Ed. 1995, 34, 2383-2385. 

3. O. Hoffmann and H.-G. Schmalz, Synlett. 1998, 12, 1426-1428. 

129 

H 

O 

OMe 

Cr(CO) 3 

1 R 1 = H R 2 = H 

2 R 1 = F R 2 = H 

3 R 1 = Me R 2 = H 

4 R 1 = OMe R 2 = H 

5 R 1 = CF 3 R 2 =H 

6 R 1 = H R 2 = F 

7 R 1 = H R 2 = Me 

8 R 1 = H R 2 = CF 3 

R 1 

R 2

P-72 


Analyzing Drug Action on Mitochondrial Targets using Functional Assays with 

Isolated Biological Active Mitochondria 

Suzan Can, a Ana Kitanovic, a Igor Kitanovic, a Annegret Hille, b Ronald Gust, b Melanie Oleszak, c 

Yvonne Geldmacher, c William S. Sheldrick, c Andreas Meyer, d Riccardo Rubbiani, d Ingo Ott d and 

Stefan Wölfl *a 

a Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Im Neuenheimer Feld 

364, 69120 Heidelberg, Germany. b Institute of Pharmacy, Department of Pharmaceutical Chemistry, 

Free university of Berlin, Germany. c Faculty of Chemistry and Biochemistry, Department of 

Analytical Chemistry, University Bochum. d Institute of Pharmaceutical Chemistry, Technische 

Universität Braunschweig, Germany. email: wolfl@uni-hd.de 

Mitochondria play crucial roles in living cells. They are not only the source of energy via oxidative 

phosphorylation and ATP synthesis, but are also an important regulators of cellular survival and in the 

control of programmed cell death. Mitochondrial damage and inhibition of the electron transfer in the 

respiratory chain can trigger the production of reactive oxygen species (ROS) and the release of 

cytochrome c. The latter initiates mitochondrial induction of apoptosis. Previous studies in intact cells 

showed that several bioorganometallic compounds significantly induced ROS formation and triggered 

cell death inducing pro-apoptotic pathways. 

To further elucidate their specific activity we wanted to investigate if mitochondria and mitochondrial 

activity are direct targets of some of these compounds. With the central role of mitochondria in the 

regulation of cell death such compounds could play an important role for anti-cancer therapy to trigger 

cell death in proliferating cancer cells. 

We isolated mitochondria from mouse liver and established a series of tests that show mitochondrial 

functionality. With these functional assays for several complexes of the respiratory chain and by 

measuring oxygen consumption we analysed the capability of various substances to influence 

respiration and selectively inhibit respiratory chain components in isolated mitochondria. Results 

revealed that some salophene iron complexes (AG Gust) and rhodium (III) polypyridyl complexes 

(AG Sheldrick) directly inhibit mitochondrial respiration. Furthermore it could be shown that 

treatment with several bioorganometallic substances lead to a release of cytochrome c and to changes 

of mitochondrial membrane potential which indicates a strong influence on the integrity of the 

mitochondrial membrane. 


130

P-73 


Asborin Meets Titanium 

Matthias Scholz a and Evamarie Hey-Hawkins* a 

a Universität Leipzig, Institute of Inorganic Chemistry, Johannisallee 29, D-04103 Leipzig, Germany, 

E-mail: mscholz@chemie.uni-leipzig.de 

Asborin, the carbaborane analogue of aspirin ® , is one of the few examples in which carbaboranes are 

used as phenyl-mimetic pharmacophores. Asborin was synthesised in a high-yield procedure starting 

from ortho-carbaborane. The compound proved to inhibit both cyclooxygenase (COX) isozymes, the 

target enzymes of aspirin. 1 The COX inhibition potential, however, was lower compared to aspirin and 

the general pharmacological profile was also different to that of aspirin. Integration of the cluster in 

place of the phenyl ring turned aspirin into a more toxic compound, which triggers apoptosis 

pathways. Asborin was cytotoxic toward several cancer cell lines and exhibited the lowest potency 

toward healthy fibroblasts. This behaviour made the carbaborane compound interesting for anticancer 

drug development. As the IC50 values obtained from the cytotoxicity assays were higher than those of 

commercial chemotherapeutic agents, the compound requires further fine-tuning of its cytotoxic 

profile. 

A promising approach to increase the antitumour activity of asborin is combination with another 

cytotoxic moiety. Therefore, we decided to modify asborin with titanium complexes, as some 

derivatives were found to be active toward several tumour cells. The most prominent anticancer 

titanium derivatives are the organometallic compound titanocene dichloride and the bioinorganic 

complex budotitane. 2 The carboxyl group and carbaborane moiety of asborin allow it to form both 

bioinorganic and organometallic titanium compounds. Coordination of asborin as carboxylate could 

displace the chloride ions in titanocene dichloride. Alternatively, instead of a cyclopentadienyl ring the 

nido carbaborane cluster can act as ligand for titanium. Thus, carbaboranes can easily be deboronated 

to give anionic nido clusters, which feature an open pentagonal plane. These anions can then form 

different metallocene analogues. 

References 

1. M. Scholz, K. Bensdorf, R. Gust, E. Hey-Hawkins, ChemMedChem. 2009, 4, 746-748. 

2. J. C. Dabrowiak: Titanium compounds for treating cancer in Metals in Medicine; 1. Ed.; Wiley: 

New York, USA, 2009; pp. 167-177. 

131

P-74 


Coordination Behavior and Spectroscopic Studies of Biologically Active 

Organotin(IV) Complexes of 2-(N-naphthylamido)benzoic Acid 

Khadija Shahid a� 

a Riphah Institute of Pharmaceutical, Sciences 7 th Avenue, G-7/4, Riphah International 

University, Islamabad-45320 Pakistan 

New organotin(IV)complexes of 2-(N-naphthylamido)benzoic acid were synthesized in 

stoichiometric ratio in anhydrous toluene under the reflux yield the organotin(IV) carboxylates with 

general formula R 4-nSnLn(R= Me, n-Bu, Ph, n-Oct, Bz and n= 2, 3). All the complexes have been 

characterized by various spectroscopic methods (IR, 1 H, 13 C, 119 Sn NMR) and mass spectrometry. 1 

Cytotoxicity of the synthesized compounds was checked against Brine-shrimp larvae. 

In vitro activities against some Gram-positive and Gram-negative bacteria and fungi were also 

determined. 2 Antimicrobial activities show that species with tetrahedral geometry in solution are 

more toxic. 3 

References 

Scheme: Synthesis of Di/Tri organotin Complexes. 

1. (a) K. Shahid, S. Ali, S. Shahzadi, J. Coord. Chem. 2009, 62(17), 2919–2926. (b) K. Shahid, S. 

Shahzadi, J. Serb Chem. Soc. 2009, 74(2), 141-154. 

2. A. Rahman, M.I. Choudhary, W.J. Thomsen, Bioassay Techniques for Drug Development; 

Hardward Academic Press, Amsterdam 2001. 

132

P-75 


Raman Microscopic Cell Uptake Studies of 

Bioactive Organometal Peptide Conjugates 

Thomas Sowik a , Eugen Edengeiser b , Martina Havenith-Newen, b and Ulrich Schatzschneider a * 

a Lehrstuhl für Anorganische Chemie I – Bioanorganische Chemie, Ruhr-Universität Bochum, 

Universitätsstr. 150, D-44801 Bochum, Germany, E-Mail: thomas.sowik@rub.de. 

b Lehrstuhl für Physikalische Chemie II, Ruhr-Universität Bochum, Universitätsstr. 150, D-44801 

Bochum, Germany. 

A major problem is the lack of molecular markers which do not influence the intracellular distribution 

and biological activity and show signals where constitutions of the cell normal do not. Raman 

microscopy, however, is a potent technique for cell imaging and drug uptake studies. 1 The C-D 

stretching vibration of deuterated compounds appears in a spectroscopic window between 2100 and 

2350 cm -1 where bio (macro) molecules do not show vibrational signals. Thus, it is possible to 

investigate the cell uptake and metabolism of these compounds. 2 Peptide bioconjugates with 

cyclopentadienylrhenium- or cyclopentadienylmangenese tricarbonyl are known for their biological 

activity depending on the peptide sequence. 3 Their analogues with deuterated metal complexes are 

promising candidates for Raman microscopy (Fig. 1). An example is sC18 with the sequence 

GLRKRLRKFRNKIKEK-NH2 which delivers metal complex bioconjugates to cancer cells. 

Rayleigh signal 

1650 

1907 

1942 

2020 

2352 

0 1000 2000 3000 4000 

Wavenumber cm -1 

3119 

Figure 1: Raman spectrum (left) of deuterated cyclopentadienylrhenium(I) tricarbonyl carbocylic acid (right). The C-D 

stretching vibrations appear at 2352 cm -1 . 

Within this work we have prepared deuterated cyclopentadienyl carboxylic acid, which was reacted 

with dirhenium decacarbonyl to deuterated cyclopentadienylrhenium(I) tricarbonyl carboxylic acid. 

Subsequently, bioconjugates were prepared and their biodistribution and cell-uptake was studied using 

Raman spectroscopy and microscopy. 

Reference 

1. C. Matthäus, T. Chernenkoa, L. Quinteroc, L. Milanb, A. Kaleb, M. Amijib, V. Torchilinb, M. 

Diema, Proc. SPIE 2008, 6991. 

2. H.-J. v. Manen, A. Lenferink, C. Otto, Anal. Chem. 2008, 80, 9576–9582. 

3. K. Meister, J. Niesel, U. Schatzschneider, N. Metzler-Nolte, D. A. Schmidt, M. Havenith, Angew. 

Chem. 2010, accepted for publication. 

133 

D 

D 

D 

COOH 

D 

Re 

CO 

OC CO

P-76 


Synthesise of New Butyl Tin(IV) Compounds and Investigation About Their 

Toxicity and Anti-inflammatory Studies 

Fatemeh Tavakolinia, a Mohammad Yousefi, a Saeed Amanpour, b Samad Mohammadnejad, b 

and Mojdeh Safari *b 

a Azad University, Shahre-rey Branch, Tehran, Iran 

b Experimental Lab, Cancer Research center, Tehran university of medicinal sciences, Tahran, Iran. 

E-mail: ftavakolinia@yahoo.com 

Chemistry of organotin(IV) complexes has developed considerably during the last 30 years, 

highlighting the synthesis of a number of complexes with interesting properties. 1-3 One of the most 

important bioinorganic chemistry research areas as regards organotin compound is the investigation 

of their cytotoxic/antitumor activities. In addition many organotin(IV) compounds have been tested for 

their in vitro activity against a large variety of tumor lines and have been found to be as effective or 

better than traditional heavy metal anticancer drugs such as Cis-platin. 4,5 In general, toxicity of 

organotin(IV) compounds seems to increase with the chain length of the organic alkyl group, which 

are often more active than aryl ones, and follow the order R3Sn> R2Sn> RSn. 6 In this research three 

new organotin(IV) complexes of the general formula R3SnŔ and R2SnŔ2 (where R=Ph, Bu, and Ŕ=1- 

Butane, 2-Butane, Ph) have been synthesized by the Grignard reaction of triphenyltin chloride with 1iodo 

butane and 2-chloro butane in 1:1 molar ratio and the reaction of dibutyltin dichloride with chloro 

benzene in 1:2 molar ratio. The resulted complexes are Ph3Sn1-Bu (1), Ph3Sn2-Bu (2), Ph2SnBu2 (3). 

The sample of synthesise of one of the complexes comes below. These new derivatives have been 

characterized by FT-TR, 1 H, 13 C, 119 Sn NMR and Mass spectroscopy. The toxicity study and antiinflammatory 

effect are going to carry out and the LD50 value is going to determine. 

ICH2CH2CH2CH3 + Mg � IMgCH2CH2CH2CH3 

IMgCH2CH2CH2CH3 + Ph3SnCl � Ph3SnCH2CH2CH2CH3 (1) + MgClI 

References 

1. M.J.Clarke, F. Zhu, D. R.Frasca, Chem. Rev. 1999, 99, 2511. 

2. J.Beckmann, K. Jurkschat, Coord. Chem. Rev. 2001, 215, 267. 

3. L.Pellerito, L.Nagy, Chem. Rev. 2002, 224, 111. 

4. M. Gielen, App. Organomet. Chem.2002, 16, 481. 

5. M. Gielen, Coord. Chem. Rev. 1996, 26, 1. 

6. D. Dc Vos, R.Willem, M. Gielen, K. E. Van Wingerden, K. K. Nooter, Net. Based drugs 1998, 5. 

134

P-77 


Water Enables Direct Palladium-Catalyzed C-allylation of Cyclic 1,3-Diones with 

Allylic Alcohols without Activators 

Shyh-Chyun Yang *a and Yi-Jen Shue a 

a Kaohsiung Medical University, School of Pharmacy, 100 Shih-Chuan 1st Road, 807, Kaohsiung, 

Taiwan. E-mail: scyang@kmu.edu.tw 

The palladium-catalyzed allylation is a powerful tool for C–C, C–N, and C–O bond formation, which 

has been widely applied to organic chemistry. We have recently disclosed a new catalytic system for 

palladium/carboxylic acid–catalyzed allylation with allylic alcohols in water as a suspension medium. 1 

Organic reactions in water have recently attracted much attention, because water is a safe and 

economical substitute for conventional organic solvent. Herein, we report that palladium-catalyzed 

ally-OH bond cleavage in the absence of activating agents. Allylation of cyclic 1,3-diones worked well 

with aromatic allylic alcohols in water and gave generally good to high yields. This is a simple and 

efficient route for C–C bond formation. 

References 

O O 

R 

Pd /P-ligand, H 2O 

OH 

R 

135 

R R 

O O + O O 

1. (a) S.-C. Yang, Y.-C. Hsu, K.-H. Gan. Tetrahedron 2006, 62, 3949-3958. (b) K.-H. Gan, C.-J. 

Jhong, S.-C. Yang, Tetrahedron 2008, 64, 1204-1212.

P-78 


In Vitro Interactions of Rhenium(III) Compounds with Phospholipids and 

Nucleic Bases Derivatives 

a Dina Y. Yegorova, b Nataliia I. Shtemenko, a Alexander V. Shtemenko 

a Department of Inorganic Chemistry, Ukrainian State Chemical Technological University, 

Gagarin Ave. 8, Dnipropetrovs’k 49005, Ukraine. E-mail: shtemenko@ukr.net, b Department 

of Biophysics and Biochemistry, Dnipropetrovs’k National University, 72 Gagarin avenue, 

Dnipropetrovs’k 49010, Ukraine 

In our previous investigations it was shown that rhenium(III) complexes had antitumor, antihemolytic 

and red blood cells stabilizing properties. 1 The important component of the integral biological activity 

of any substance is its ability to cross the cell membrane and to react with nuclear bases. Investigations 

of the interaction between rhenium(III) cluster complexes and phospholipids as one of the main 

components of a cell membrane and nuclear bases is of great importance as may help to understand 

the mechanism of their action and to find further synthetic directions. 

In this work the experiments were accomplished with cluster rhenium(III) compounds with common 

formulas: [Bu4N]2×[Re2Cl8], cis-[Re2(CH3COO)2Cl4]×2H2O, trans-Re2(C2H5COO)2Cl4 , 

Re2(RCOO)3Cl3, Re2(RCOO)4Cl2, where R - CH3, C2H5, i-C3H7, C10H15; with phospholipids: 

phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine and nuclear bases derivatives: 9methyladenin 

and 9-methylguanin. The electronic absorbtion spectra of mixtures of the substances 

were studied. 

According to the obtained spectra the strongest interaction was found with phosphatidylholine among 

other main phospholipids of cells membrane. It was shown that the mechanism of interaction 

depended on the structural type of cluster rhenium(III) complexes. In the case of tetra-μ-carboxylates 

bridged equatorial carboxylic groups were replaced by phosphate groups of phosphatidylholine with 

following formation of monodentate derivatives. During interaction of phosphatidylholine with cistetrachlorodi-μ-carboxylates 

of dirhenium(III) replacement of terminal chlorides by 

phosphatidylholine ligands with formation of monodentate derivatives with the change of the 

previous structural type was shown. The same interactions were shown to be realized during formation 

of nanoliposomes of cluster rhenium(III) compounds and phosphatidylholine. 

Hydrolytic process of the complex rhenium(III) compounds was shown to take place in water 

solutions, that’s why nanoliposomal forms of rhenium(III) complex compounds were obtained from 

phosphatidylholine to prolong their therapeutic effect. It was shown that the coordination of phosphate 

groups of phosphatidylholine to the cluster centre (unit) of Re2 6+ provided prevention of hydrolytic 

process and increased the stability of these compounds. 

Bidentate coordination of the 9 MeA to equatorial position of the cluster Re2 6+ centre through N1/N6 

atoms of the nucleic base heterocidic ring was shown. Another type of coordination was shown for 

Guanine derivative: 9MeG coordinated by monodentate mode to axial position of the Re2 6+ centre only 

through N1 atom of the heterocidic ring. The mechanism of interaction between nucleic bases and 

rhenium(III) compounds was different in comparison with the same for platinides that explained the 

effectiveness of the Rhenium – Platinum antitumor system in the earlier experiments in vivo. 

References 

1. (a) N. Shtemenko, P. Collery, A. Shtemenko, Anticancer Res. 2007, 27, 2487-2492. (b) A. 

Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, E. Zabitskaya, A. Golichenko, Dalton Trans. 

2009, 5132-5136. 

136

P-79 


Tris(pyrazolyl)borates as Versatile Ligands in the Synthesis of Bioorganometallic 

Compounds 

Johannes Zagermann, a Matthew C. Kuchta, a Klaus Merz, a Nils Metzler-Nolte a* 

a Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstraße 150, 

44801 Bochum, Germany, Johannes.Zagermann@rub.de 

While cyclopentadienyl (Cp) containing compounds such as ferrocene have found various applications 

in bioorganometallic chemistry, little work is found concerning analogue compounds containing Cp 

surrogates. As such, we have been interested in exploiting the rich coordination chemistry of 

tris(pyrazolyl)borate (Tp) ligands for the synthesis of bioconjugates with possible applications in 

biomedical, electrochemical or spectroscopical studies. 

We describe the synthesis and characterization of mixed ligand (Cp/Tp) and (Tp/Tp') ruthenium 

sandwich compounds, 1 both incorporating a “third-generation” p-BrC6H4Tp (Tp') ligand, 2 and their 

application in the formation of peptide bioconjugates. More recently, we utilized iodocarbonyltungsten 

complexes containing a regular Tp* ligand to label peptides via η 2 -coordinated alkyne ligands 

including the unusual amino acid propargylglycine. 3 

References 

1. (a) J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, J. Organomet. Chem. 2009, 694, 862- 

867. 

(b) J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, manuscript in preparation. 

2. J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, Eur. J. Inorg. Chem. 2009, 5407-5412. 

3. J. Zagermann, K. Merz, N. Metzler-Nolte, Organometallics 2009, 28, 5090-5095. 

137

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Synthesis of Some Metal Dye-complexes as Antimicrobial Agents 

Ibrahim F. Zeid *a and Husein A. Agwa a 

a Department of Chemistry, Faculty of Science, Monoufia University Shibin El-Koam, Egypt 

E-mail: ifzeid@hotmail.co.uk 

An enormous number of 4-arylazo-2-pyrazolin-5-ones has been reported in the literature as dyes of 

commercial value. The reaction of 4-arylazo-l-phenyl-3 -(methyl or phenyl)-2-pyrazolin-5-ones with 

copper and cobalt salts resulted in the formation of some new metal dye complexes. 1,2 The importance 

of the newly synthesized complexes as antimicrobial agents has been discussed. 

References 

R 

N 

N 

Ph 

1 

N=NAr 

O 

R 

N 

N 

Ph 

N=NAr 

O 

1. F. A. Amer, A. H. Harhash, M. A. Metwally, Z .Natuforsch. 1977, 32b, 943. 

2. A. A. Fadda, M. A. Metwally. A.M. Khalil, Indian J. Text. 1983, 8, 82. 

3. M. A. Metwally, A. A. Fadda, H. M. Hassan, E. Afsah, Org. Prep. Proc. Int. 1985, 17, 198. 

4. I. F. Zeid, M.T. Omar, A. A. Makhlouf, M. M. Kamel, N. M. Khalifa, Egypt. J. Pharm. Sci. 1996, 

37, 251. 

138 

M 

2 

O 

ArN=N 

Ph 

N 

N 

R

P-81 


Apoptosis induction and cytotoxicity by metalbased drugs: 

lights and shadows of DNA 

Gianni Sava a,b and Alberta Bergamo b 

a University of Trieste, Department of Life Sciences, via L. Giorgieri 7, 34127, Trieste, Italy. b Callerio 

Foundation Onlus, via A. Fleming 22-31, 34127, Trieste, Italy. E-mail: gsava@units.it 

Cisplatin is a well known DNA-damaging agent and the current thinking is that DNA platination 

(DNA-adduct formation) is an essential first step in the cytotoxic activity of the drug. Information 

about the chemistry of the platinum compounds and correlations of their structures with anticancer 

activity have provided guidance for the design of novel anticancer drug candidates based on the 

proposed mechanisms of action. 1 The question is: DNA-adduct formation guided synthesis of metalbased 

anticancer drugs is a real concept or a misleading interpretation? The mechanism(s) whereby the 

DNA adducts kill cells is not fully understood. One potentially important way by which cisplatin- 

DNA adducts may kill cells is by induction of programmed cell death or apoptosis (Figure 1). 2,3 

From: to: 

Figure 1. types of DNA adduct formation of platinum drugs: (a) interstrand cross-link, (b) 1,2intrastrand 

cross-link, (c) 1,3-intrastrand crosslink, (d) protein-DNA cross-link (adapted from Lit. 2) 

However, these concepts are not sufficient to account for the particular effectiveness of the most 

important platinum drugs in cancer therapy where cisplatin and carboplatin (two drugs with a rather 

different chemistry) are active on the same tumours, oxaliplatin is active on colorectal tumours and 

satraplatin (the emerging oral platinum drug) is active on prostate cancer. None of these tumours were 

selected a priori as the targets for these drugs. Then, how focusing on the ligands that allow DNA 

binding or to get insensitivity to acquired resistance, may help researchers to understand what to take 

into consideration to design the expected more potent, more selective and less toxic new metal-based 

antitumour drugs? Apoptosis and cell death is not simply related to DNA binding properties as shown 

by the many biological and targeted drugs emerged in the last years which killed cells by apoptoptic 

mechanisms following interactions with protein components of important cellular pathways. Given 

that cisplatin and also many platinum drugs have a poor capacity to enter the nucleus compartment (in 

the case of cisplatin almost 99% of the cellular drug is in the cytoplasm) the focus should be directed 

on what are the final destinations of all these platinum molecules in this protein-rich compartment. As 

an example, interesting data are emerging on HSP90 block by cisplatin, a phenomenon that could 

account for many apoptotic cytotoxicities observed. This work was done in the framework of COST 

D39 – WG3. 

References 

1. K.S. Lovejoy, S.J. Lippard, Dalton Trans. 2009, 48, 10651-10659. 

2. A. Eastman: The mechanism of action of cisplatin: From adducts to apoptosis in: Cisplatin. 

Chemistry and Biochemistry of a Leading Anticancer Drug; B. Lippert, Ed.; Wiley-VCH: Basel, 

Switzerland, 1999, pp. 111–134. 

3. R.C. Todd, S.J. Lippard, Metallomics 2010, 4, 280-291. 

139

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Selective Recognition of Actinides by Protein-Based Reagents 

Salih Özçubukçu, a Seraphine V. Wegner, a Kalyaneswar Mandal, b Stephen B. H. Kent, b 

Mark P. Jensen, c and Chuan He *a 

a The University of Chicago, Department of Chemistry, 60637, Chicago, IL, USA. b The University of 

Chicago, Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for 

Biophysical Dynamics, 60637, Chicago, IL, USA. c Argonne National Laboratory, Chemical Sciences 

and Engineering Division, 60439, IL, USA,. 

e-mail: chuanhe@uchicago.edu 

It is generally accepted that trivalent actinides prefer softer chelating atoms such as sulfur rather than 

oxygen; hence selective separation of trivalent actinides from trivalent lanthanides can be obtained by 

soft-donor ligands. 

Barbara Imperiali and her coworkers have developed a series of peptides, called lanthanide binding tag 

(LBT) which selectively binds lanthanide ions with high affinities 1 . This pre-organized ligand template 

provides an ideal system to study these long standing questions regarding separate trivalent actinides 

from trivalent lanthanides. Pre-organization of the ligands by the peptide scaffold provides high 

binding affinity. We can redesign these small peptides with nitrogen- and sulfur- based ligands to 

provide selectivity. We plan to systematically screen ligand types and geometries to achieve selective 

binding of actinides over lanthanides (Figure 1). 

References 

1. M. Nitz, M. Sherawat, K. J. Franz, E. Peisach, K. N. Allen, B. Imperiali, Angew. Chem. Int. Ed. 

2004, 43, 3682-3685. 

140

P-83 


Iridium Complex with Antiangiogenic Properties 

Alexander Wilbuer, a D. H. Vlecken, b D. J. Schmitz, b C. P. Bagowski, b and Erik Meggers* a 

a Philipps Universität Marburg, Fachbereich Chemie, Hans-Meerwein Str., 35032 Marburg, 

Germany. b Leiden University, Institute of Biology, Wassenaarseweg 64, 

2333 AL Leiden, The Netherlands. Wilbuer@chemie.uni-marburg.de 

Substitutionally inert metal complexes are promising emerging scaffolds for targeting enzyme active 

sites. 1 Our group has demonstrated over the last five years that inert ruthenium(II) complexes can 

serve as highly selective nanomolar and even picomolar inhibitors of protein kinases. 2 Octahedral 

metal coordination geometries in particular offer new gateways to design rigid, globular molecules 

with defined shapes that can fill protein pockets such as enzyme active sites in a unique fashion. 3 

Although most of our previous efforts were focused on ruthenium(II) complexes, we envisioned that 

octahedral iridium(III) complexes might be interesting scaffolds for two reasons: First, coordinative 

bonds with Ir(III) tend to be very inert 4 and therefore Ir(III) complexes should be able to serve as 

stable scaffolds for the design of enzyme inhibitors. 5 Second, octahedral Ir(III) complexes can be 

accessed from square planar Ir(I) complexes by stereospecific oxidative addition reactions. 6 Here we 

present the discovery of an octahedral iridium(III) complex, synthesized through oxidative addition as 

the key synthetic step. The organometallic compound functions as a low nanomolar and highly 

selective inhibitor of the protein kinase Flt4, also known as VEGFR-3 (vascular endothelial growth 

factor receptor 3). Flt4 is involved in angiogenesis and lymphangiogenesis and we were able to 

demonstrate that this iridium complex can indeed interfere with the development of blood vessels in 

vivo in two different zebrafish angiogenesis models. 

References 

1. E. Meggers, Curr. Opin. Chem. Biol. 2007, 11, 287-292. 

2. E. Meggers, G. E. Atilla-Gokcumen, H. Bregman, Synlett 2007, 8, 1177-1189. 

3. J. Maksimoska, L. Feng, K. Harms, J. Am. Chem. Soc. 2008, 130, 15764-15765. 

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141

P-84 


New Oxorhenium(V) Complex with Aminothiazole Ligand, and Radiochemical 

Behavior of its Oxotechnetium(V) Complex Analog 

Norah S. Al-Hokbany, a* R.M. Mahfouz, a and I.J. Al-Jammaz b 

a King Saud University, Department of Chemistry, College of Science, P.O.Box 2455, Riyadh, 11451 

Kingdom of Saudi Arabia. b Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist 

Hospital and Research Center. P.O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia. 

Tel:+966 1 4772245; Fax: +966 1 4772245. e-mail: nhokbany@ksu.edu.sa 

A [ReO(amino)2OH] complex was successfully synthesized by ligand exchange method of 

oxorhenuim gluconate with aminothiazole ligand. Geometry optimization of complex has been carried 

out using DFT at the B3LYP/LANL2DZ functional in singlet state. B3LYP predicted infrared 

spectrum of geometrical optimized structure using the same level of the theory and the same basis set 

showed good agreement with experimentally observed values. The complex has been characterized 

using elemental analysis and different spectroscopic techniques (IR, UV-Vis, NMR and MS). 

At the technetium tracer level, the 99m TcO-complex has been synthesized by two methods ( 99m Tcgluconate 

as precursor; direct reduction). The radiochemical purity of the complex was over 95% as 

measured by thin layer chromatography. In vitro studies showed that the complex possessed good 

stability under physiological conditions. Its partition coefficient indicated that it was a hydrophilic 

complex. The electrophoresis results showed the complex was neutral. Normal biodistribution of 99m 

Tc complex, exhibit high lung, liver and spleen uptake (27%, 11%, and 12%, respectively). Blood and 

lung clearance was quite fast (% injection dose in blood and lungs 0.36% and 0.18%, respectively at 1 

hr post-injection), while liver activity remained high for a longer period (% injection dose 12% at 1 hr 

post-injection). The radioactivity from the novel technetium complex was excreted mainly through the 

hepatobiliary system (35% at 1 h post-injection) and partially kidney. 

References 

pH=9 

r.t 

45min 

99m TcO4 - 

NaBH 4 

Na-gluconate 

SnCl2. 2H2O 99m TcO(gluc)2 - 

+ 

NH 

O 

M 

N S 

OH 

N 

S NH2 S 

HN 

were M = Re, 99m Tc 

142 

N 

ReO 4 - 

Na-gluconate 

SnCl 2. 2H 2O 

ReO(gluconate) 2 - 

1. P. Bouziotis, D. Papagiannopoulou, I. Pirmettis, M. Pelecanou, C.P. Raptopoulou, C.I. 

Stassinopoulou, A. Terzis, M. Friebe, H. Spies, M. Papadopoulos, E. Chiotellis, Inorg. Chim. Acta 

2001, 320, 174-177. 

2. H. Zhang, M. Dai, C. Qi, X. Guo, Appl. Radiat. Isot. 2004, 60, 643-651. 

3. B. Dhara, P. Chattopadhyay, Appl. Radiat. Isot. 2005, 62, 729-735. 

4. K. Schwochau, Technetium Chemistry and Radiopharmaceutical Applications, Wiley-VCH, 

Weinheim, 2000.


Participants 

143

Sergey Abramkin 

Universität Wien, Austria 

sergey.abramkin@univie.ac.at 

Oladipo Ademola 

Lautech, Nigeria 

suspyo@yahoo.com 


Ebenezer Aidoo 

University of South Africa, South Africa 

lincollnn@yahoo.com 

Prof. Dr. Roger Alberto 

Univerität Zürich, Switzerland 

ariel@aci.uzh.ch 

Hamed Alborzinia 

Universität Heidelberg, Germany 

hamed.alborzinia@uni-heidelberg.de 

Dr. Noura Al-Hokbany 

King Saud University, Saudi Arabia 

nhokbany@ksu.edu.sa 

Dr. Wee Han Ang 

National University of Singapore, Singapore 

chmawh@nus.edu.sg 

Anusch Arezki 

ENSCP, France 

anusch-arezki@chimie-paristech.fr 

Dr. Braja Gopal Bag 

Vidyasagar University, India 

bgopalbag@yahoo.co.in 

Nicolas Barry 

University of Neuchatel, Switzerland 

nicolas.barry@unine.ch 

Prof. Dr. Wolfgang Beck 

Ludwig-Maximilians-University München, Germany 

wbe@cup.uni-muenchen.de 

Samaneh Beheshti 

University of Western Ontario, Canada 

sbehesh@uwo.ca 

Dr. Alberta Bergamo 

Callerio Foundation, Italy 

a.bergamo@callerio.org 

144


Ruth Bieda 

Ruhr-Universität Bochum, Germany 

ruth.bieda@rub.de 

Sebastian Blanck 

Universität Marburg, Germany 

sebastian.blanck@chemie.uni-marburg.de 

Dmytro Bobukhov 

Ukrainian State Chemical Technology University, Ukraine 

dbobukhov@googlemail.com 

Dr. Diane Bouvet-Muller 

ICMPE Paris 12, France 

muller@u-pec.fr 

Adam Boynton 

Trinity College, USA 

timothy.curran@trincoll.edu 

Nadine Brückmann 

Universität Düsseldorf, Germany 

brueckmn@uni-duesseldorf.de 

Prof. Dr. Peter Buglyo 

University of Debrecen, Hungary 

buglyo@delfin.unideb.hu 

Daniel Can 

Universität Zürich, Switzerland 

daniel.can@aci.uzh.ch 

Suzan Can 


suz.c@gmx.de 

Dr. Angela Casini 

EPFL, Switzerland 

angela.casini@epfl.ch 

Prinessa Chellan 

University of Cape Town, South Africa 

prinessa.chellan@uct.ac.za 

Dr. Joao Correia 

ITN, Portugal 

jgalamba@itn.pt 

Prof. Dr. Timothy Curran 


timothy.curran@trincoll.edu 

145

Tensim Dallagi 

ENSCP, France 

t.dallegi@laposte.net 


Prof. Dr. Marcetta Darensbourg 

Texas A&M University, USA 

marcetta@mail.chem.tamu.edu 

Prof. Dr. Roman Dembinski 

Oakland University, USA 

dembinsk@oakland.edu 

Jan Dittrich 


jan.dittrich@rub.de 

Prof. Dr. Holger Dobbek 

Humboldt-Universität zu Berlin, Germany 

holger.dobbek@biologie.hu-berlin.de 

Christine Doffek 


christine.doffek@rub.de 

Gregor Dördelmann 


gregor.doerdelmann@rub.de 

Anica Dose 

University of Kent, Great Britain 

ad308@kent.ac.uk 

Prof. Dr. Paul Dyson 


paul.dyson@epfl.ch 

Dr. Johannes Eble 

Universität Frankfurt, Germany 

eble@med.uni-frankfurt.de 

Prof. Dr. Richard Fish 

Lawrence Berkeley National Laboratory, USA 

rhf@lbl.gov 

Ying Fu 

University of Warwick, Great Britain 

fuyingpku@gmail.com 

Dr. Christian Gaiddon 

University of Strasbourg, France 

gaiddon@unistra.fr 

146

Dr. Gilles Gasser 


gilles.gasser@aci.uzh.ch 


Luca Gaviglio 

University of Piemonte Orientale, Italy 

luca.gaviglio@mfn.unipmn.it 

Yvonne Geldmacher 


yvonne.geldmacher@rub.de 

Prof. Dr. Roberto Gobetto 

University of Torino, Italy 

roberto.gobetto@unito.it 

Meral Gormen 

ENSCP, France 

meral-gormen@chimie-paristech.fr 

Annika Groß 


annika.gross@rub.de 

Prof. Dr. Ronald Gust 

Freie Universität Berlin, Germany 

rgust@zedat.fu-berlin.de 

Frauke Hackenberg 


frauke.hackenberg@rub.de 

Didier Hamels 

ENSCP, France 

didier.hamels@hotmail.fr 

PD Dr. Christian Hartinger 

Universität Wien, Austria 

christian.hartinger@univie.ac.at 

Masoumeh Hazratilivari 

Iran 

zazoli49@yahoo.com 

Dr. Jörg Henig 


joerg.henig@rub.de 

Prof. Dr. Richard Herrick 

College of the Holy Cross, USA 

rherrick@holycross.edu 

147

Prof. Dr. Toshikazu Hirao 

Osaka University, Japan 

hirao@chem.eng.osaka-u.ac.jp 

Dr. Elizabeth Hillard 

ENSCP, France 

elizabethhillary@yahoo.com 


Pavlo Holenya 


Wanning Hu 


wanning.hu@rub.de 

Dr. Jamie Humphrey 

Royal Society of Chemistry, Great Britain 

humphreyj@rsc.org 

Nina Hüsken 


nina.huesken@rub.de 

Maxim Izumsky 


maksimizumsky@gmail.com 

Kartin Jäger 

Forschungszentrum Rossendorf, Germany 

k.jaeger@fzd.de 

Rajkumar Jana 

Universität Stuttgart, Germany 

jana@iac.uni-stuttgart.de 

Prof. Dr. Gerard Jaouen 

ENSCP, France 

gerard-jaouen@chimie-paristech.fr 

Prof. Dr. Andres Jäschke 


jaeschke@uni-hd.de 

Dr. Violeta Jevtovic 

University of Novi Sad, Serbia 

violeta.jevtovic@dh.uns.ac.rs 

Prof. Dr. Jorge Jios 

Universidad Nacional de La Plata 

Argentina 

jijios@quimica.unip.edu.ar 

148


Prof. Dr. Kenneth Kam-Wing Lo 

City University of Hong Kong, Hong Kong 

bhkenlo@cityu.edu.hk 

Christine Kasper 


christine.kasper@rub.de 

Syed Gohar Taqi Kazimi 

University of Sargodha, Pakistan 

gohartaqi@hotmail.com 

Dr. Srecko Kirin 

Institut Ruđer Bošković, Croatia 

srecko.kirin@irb.hr 

Dr. Igor Kitanovic 


igor.kitanovic@urz.uni-heidelberg.de 

Malte Kokoschka 


malte.kokoschka@rub.de 

Dr. Konrad Kowalski 

University of Lodz, Poland 

kondor15@wp.pl 

Prof. Dr. Heinz-Bernhard Kraatz 


hkraatz@uwo.ca 

Dr. Erik Kriel 

Mintek , South Africa 

erikk@mintek.co.za 

Dr. Lukas Kromer 

ITQB-UNL, Portugal 

kromer@itqb.unl.pt 

Dr. Peter Kunz 


peter.kunz@uni-duesseldorf.de 

See Mun Lee 

University of Malaya, Malaysia 

annieleesm@gmail.com 

Prof. Dr. Emanuela Licandro 

University of Milano, Italy 

emanuela.licandro@unimi.it 

149


Zhe Liu 

University of Warwick, Great Britain 

z.liu.2@warwick.ac.uk 

Olessya Loiko 

Karaganda State University, Kazakhstan 

olessya0905@gmail.com 

Dr. Jason Lynam 

University of York, Great Britain 

jml12@york.ac.uk 

Prof. Dr. Stefano Maiorana 

University of Milano, Italy 

stefano.maiorana@unimi.it 

Basudev Maity 

Indian Institute of Science Bangalore, India 

ipcbasudev@gmail.com 

Sergey Malinkin 

Kiev National Taras Shevchenko University, Ukraine 

malinachem@mail.ru 

Dr. Sanela Martic 


smartic@uwo.ca 

Niall McGuinness 

National University of Ireland, Irland 

nmguinness@hotmail.com 

Thomas McTeague 


Prof. Dr. Eric Meggers 


meggers@chemie.uni-marburg.de 

Sandra Mieranz 

Freie Universität Berlin 

Germany 

Prof. Dr. Morten Meldal 

Carlsberg Laboratory, Denmark 

mpm@crc.dk 

Prof. Dr. Mohamed Metwally 

University of Mansoura, Egypt 

mamegs@mans.edu.eg 

150


Prof. Dr. Nils Metzler-Nolte 


nils.metzler-nolte@rub.de 

Andreas Meyer 

TU Braunschweig, Germany 

andreas.meyer@tu-bs.de 

Stefan Mollin 


stefan-mollin@web.de 

Jean-Philippe Monserrat 

ENSCP, France 

jean-philippe-monserrat@chimie-paristech.fr 

Prof. Dr. Toshiyuki Moriuchi 

Osaka University, Japan 

moriuchi@chem.eng.osaka-u.ac.jp 

Prof. Dr. Orde Munro 

University of KwaZulu-Natal, South Africa 

munroo@ukzn.ac.za 

Ali Nazif 


alinazif@hotmail.com 

Dr. Alexey Nazarov 


alexey.nazarov@epfl.ch 

Johanna Niesel 


johanna.niesel@rub.de 

Dr. Stephan Niland 

Universität Frankfurt, Germany 

niland@med.uni-frankfurt.de 

Anna-Luisa Noffke 


anna-louisa.noffke@uni-duesseldorf.de 

Luciano Oehninger 


oehninger@gmail.com 

Dr. Melanie Oleszak 


m.oleszak@gmx.de 

151

Obiora Augustine Orakwue 

Hyqid Nigeria Ltd., Nigeria 

hyqidenergy@gmail.com 


Prof. Dr. Chris Orvig 

University of British Columbia, Canada 

orvig@chem.ubc.ca 

Prof. Dr. Domenico Osella 

University of Alessandria, Italy 

domenico.osella@mfn.unipmn.it 

Prof. Dr. Ingo Ott 


ingo.ott@tu-bs.de 

Dr. Salih Özçubukçu 

University of Chicago, USA 

salih@uchicago.edu 

Prof. Dr. Mallayan Palaniandavar 

Bharathidasan University, India 

palanim51@yahoo.com 

Malay Patra 


malay.piu@gmail.com 

Dr. Andrew Phillips 

University College Dublin, Ireland 

andrew.phillips@ucd.ie 

Hendrik Pfeiffer 


hendrik.pfeiffer@rub.de 

Anais Pitto-Barry 

Universität Neuchatel, Switzerland 

anais.pitto-barry@unine.ch 

Dr. Nicolas Plumere 


nicolas.plumere@rub.de 

Maria Proetto 

Freie Universität Berlin, Germany 

Lukasz Raszeja 

Ruhr-Universität Bochum, Gmany 

lukaszraszeja@aol.com 

152


Mariia Randarevych 


m_randarevich@mail.ru 

Prof. Dr. Mauro Ravera 

Universtiy of Piemonte Orientale, Italy 

mauro.ravera@mfn.unipmn.it 

Prof. Dr. Charles Riordan 

University of Delaware, USA 

riordan@udel.edu 

Steffen Romanski 

Universität zu Köln, Germany 

romansks@uni-koeln.de 

Prof. Dr. Edward Rosenberg 

University of Montana Missoula, USA 

edward.rosenberg@mso.umt.edu 

Riccardo Rubbiani 


r.rubbiani@tu-bs.fr 

Dr. Bogna Rudolf 

University of Lodz, Poland 

brudolf@chemia.uni.lodz.pl 

Mojdeh Safari 

Azad University, Iran 

msafari96@yahoo.com 

Hamid Samouei 

Shiraz University, Iran 

samouei@gmai.com 

Prof. Dr. Gianni Sava 

Callerio Foundation, Italy 

g.sava@callerio.org 

Aroonchai Saiai 


asaiai@smail.uni-koeln.de 

Dr. Ulrich Schatzschneider 


ulrich.schatzschneider@rub.de 

Prof. Dr. Hans-Günther Schmalz 


schmalz@uni-koeln.de 

153


Matthias Scholz 

Universität Leipzig, Germany 

mscholz@chemie.uni-leipzig.de 

Julia Schur 


j.schur@tu-bs.de 

Dr. Brigitte Schwederski 

Uni Stuttgart, Germany 

schwederski@iac.uni-stuttgart.de 

Dr. Khadija Shahid 

Riphah International University, Pakistan 

khadijajee@yahoo.com 

Marjan Shahmir 

Amirkabir University, Iran 

marjanshahmir@yahoo.com 

Prof. Dr. William Sheldrick 


william.sheldrick@ruhr-uni-bochum.de 

Prof. Dr. Alexander Shtemenko 


shtemenko@ukr.net 

Prof. Dr. Nataliia Shtemenko 


n.shtemenko@i.ua 

Dr. Gregory Smith 

University of Cape Town, South Africa 

gregory.smith@uct.ac.za 

Thomas Sowik 


thomas.sowik@rub.de 

Katrin Splith 

Universität Leipzig, Germany 

splith@uni-leipzig.de 

Robert Ssekanyonyi 

Kiriibwa AIDS Caring Center, Uganda 

rebeccanawanji@yahoo.com 

Marilena Stefanopoulou 


stef_point@hotmail.com 

154


Dr. Pratima Srivastava 

ENSCP, France 

pratima-srivastava@chimie-paristech.fr 

Dr. Svetlana Strashnova 

People's Friendship University of Russia, Russia 

sstrashnova@mail.ru 

Prof. Dr. Georg Süss-Fink 

Universität Neuchatel, Switzerland 

georg.suess-fink@unine.ch 

Prof. Dr. Matthias Tacke 

University College Dublin, Ireland 

matthias.tacke@ucd.ie 

Fatemeh Tavakolinia 

Azad University, Iran 

ftavakolinia@yahoo.com 

Dr. Siden Top 

ENSCP, France 

siden-top@chimie-paristech.fr 

Prof. Dr. John Valliant 

McMaster University, Canada 

valliant@mcmaster.ca 

Prof. Dr. Gerard van Koten 

Utrecht University, The Netherlands 

g.vankoten@uu.nl 

Dr. Anne Vessieres 

ENSCP, France 

a-vessieres@chimie-paristech.fr 

Prof. Dr. Yoshihito Watanabe 

Nagoya University, Japan 

yoshi@nucc.cc.nagoya-u.ac.jp 

Prof. Dr. Wolfgang Weigand 

Universität Jena, Germany 

wolfgang.weigand@uni-jena.de 

Alexander Wilbuer 


wilbuer@chemie.uni-marburg.de 

Dr. Dirk Wolters 


dirk.wolters@rub.de 

155


Prof. Dr. Stefan Wölfl 


wolfl@uni-hd.de 

Dr. Teck Tian Wong 

Nanyang Techological University, Singapore 

nhswtt@nus.edu.sg 

Dr. Yaw-Kai Yan 

Nanyang Techological University, Singapore 

yawkai.yan@nie.edu.sg 

Prof. Dr. Shyh-Chyun Yang 

Kaohsiung Medical University, Taiwan 

scyang@kmu.edu.tw 

Dina Yegorova 


dino4ka_ego@ukr.net 

Kateryna Zablotska 


pragma8@i.ua 

Johannes Zagermann 


johannes.zagermann@rub.de 

Dr. Mohammad Ali Zazouli 

Iran 

zazoli49@yahoo.com 

Prof. Dr. Ibrahim Zeid 

Monoufia University, Egypt 

ifzeid@hotmail.co.uk 

Macolm Zimbron 

Universität Basel, Switzerland 

malcolm.zimbron@unibas.ch 

Dr. Fabio Zobi 


fzobi@aci.uzh.ch 

156

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