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Book of Abstracts - Ruhr-Universität Bochum

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P-51<br />

ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />

The Synthesis and Characterization <strong>of</strong> Aqueous and Organic Soluble, Acid<br />

Selective Cytotoxic Ruthenium Anticancer Compounds<br />

Paul J. Dyson, a Olivier Zava, a David J. Kavanagh, b and Andrew D. Phillips* b<br />

a Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Sciences et Ingénierie Chimiques,<br />

CH-1015, Lausanne, Switzerland. b University College Dublin, School <strong>of</strong> Chemistry and Chemical<br />

Biology, Belfield, Dublin 4 , Ireland.E-mail: andrew.phillips@ucd.ie<br />

From the serendipitous discovery <strong>of</strong> cisplatin as an anticancer agent by Rosenberg in 1965, 1 there has<br />

been considerable interest in the field <strong>of</strong> metallopharmaceuticals. Currently only two further platinum<br />

complexes have received worldwide application in cancer treatment, Oxaliplatin and Carboplatin.<br />

Recently, organometallic ruthenium complexes have attracted greater attention as potential antitumour<br />

reagents 2-4 and systems featuring oxidation states <strong>of</strong> +2 and +3 have entered clinical trials. 5<br />

These Ru compounds (i and ii) are relatively non-toxic in comparison to platinum compounds and the<br />

mode <strong>of</strong> inducing apoptosis differs significantly from cisplatin. Therefore, Ru-based pharmaceuticals<br />

<strong>of</strong>fer valuable alternatives that may overcome Pt resistant tumours and alleviate problematic sideeffects<br />

observed with other chemotherapeutic drugs.<br />

This project focuses on the synthesis <strong>of</strong> water soluble, selective and adaptable ruthenium(II)<br />

complexes (iii) employing a mixed ligand set that convey a number <strong>of</strong> useful properties important for<br />

metallo-pharmaceuticals. The oxygen-stable phosphine, PTA (1,3,5-triaza-7-phosphaadamantane)<br />

confers water solubility, while the � 5 -coordinated anionic C5H5 group provides the necessary<br />

lipophilicity for passive cell transport. Uniquely, the bidentate triazapentadienyl ligand allows for the<br />

‘fine-tuning’ <strong>of</strong> hydrolysis behaviour by alternating the α-R groups and has proven more stable than<br />

the related Ru complexes (ii). Moreover, the triazapentadienyl ligand in compound iii imparts<br />

additional cytotoxicity as observed in previous work on similar � 6 -C6H6 Ru chloro β-diketiminates<br />

(iv). Finally, we will present our latest research which discusses the further adaption <strong>of</strong> complexes <strong>of</strong><br />

type iv towards long term biological stability and increased cytotoxicity.<br />

References<br />

(i) (ii) (iii) (iv)<br />

1. B. Rosenberg, L. Van Camp, T. Krigas. Nature. 1965, 205, 698.<br />

2. P. J. Dyson, A. D. Phillips. Organometallics. 2009, 28, 5061.<br />

3. B K. Keppler, K. Jakupec. Organometallics. 2008, 27, 2405.<br />

4. G. Sava, P. J. Dyson,. Int. J. Oncology. 2008, 33, 1281.<br />

5. (a) C. G. Hartinger, B. K. Keppler, J. Inorg. Biochem. 2006, 100, 891. (b) H. M. Schellens, J. M.<br />

Rademaker-Lakhai. Clin Cancer Res. 2004, 10, 3717.<br />

6. A. D. Phillips, O. Zava, R. Scopelitti, A. A. Nazarov, P. J. Dyson. Organometallics. 2010, 29, 417.<br />

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