Book of Abstracts - Ruhr-Universität Bochum

P-51
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
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