ISBN: 978-83-60043-10-3 - eurobic9

Eurobic9, 2-6 September, 2008, Wrocław, Poland
KL14. Metal Anticancer Complexes with Novel Mechanisms of Action
P.J. Sadler
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK
Metal complexes provide versatile platforms for the design of anticancer complexes with novel mechanisms of
action [1].
Photoactivated platinum complexes offer potential advantages over conventional platinum anticancer drugs such
as cisplatin [2]. Potentially they can be activated locally and selectively in the cancer cells and unwanted toxic
side-effects can be reduced. Kinetically-inert platinum(IV) prodrugs are suitable candidates. Diazido Pt(IV)
complexes are stable in the dark and when photoactivated under certain conditions, can be more potent towards
cancer cells than cisplatin. Moreover they can form novel lesions on DNA [3].
Organometallic half-sandwich ruthenium(II) arene anticancer complexes can bind to DNA after activation not
only by hydrolysis [4, 5], but also by ligand-based redox reactions. Two examples of such redox activation will
be discussed. The first involving oxidation of coordinated thiolates, formation of unusual sulfenato adducts and
an unexpected role for glutathione [6, 7], and the second, ligand-based reduction, the catalytic oxidation of
glutathione and production of reactive oxygen species in cancer cells [8]. Extended arenes in these complexes
can behave as novel DNA intercalators [9, 10].
The subtle differences between ruthenium and osmium involving ligand exchange rates and properties of
coordinated ligands present challenges in designing osmium analogues of active ruthenium arene anticancer
complexes. Our progress in achieving this [11, 12] will be discussed.
Acknowledgements: I thank my research group and our collaborators for their contributions to this work, the
EC, EPSRC, BBSRC, Wellcome Trust and MRC for funding, and members of COST Action D39 for stimulating
discussions.
References:
[1] P.C.A. Bruijnincx, P.J. Sadler, Curr. Opin. Chem. Biol. 12, 197 (2008).
[2] P.J. Bednarski, F.S. Mackay, P.J. Sadler, Anticancer Agents in. Med. Chem. 7, 75 (2007).
[3] F.S. Mackay, J.A. Woods, P. Heringová, J. Kaspárková, A.M. Pizarro, S.A. Moggach, S. Parsons, V. Brabec,
P.J. Sadler, Proc. Natl. Acad. Sci. USA 104, 20743 (2007).
[4] Y.-K. Yan, M. Melchart, A. Habtemariam, P.J. Sadler, Chem. Commun. 4764 (2005).
[5] F. Wang, A. Habtemariam, E.P.L. van der Geer, R. Fernández, M. Melchart, R.J. Deeth, R. Aird, S.
Guichard, F.P.A. Fabbiani, P. Lozano-Casal, I.D.H. Oswald, D.I. Jodrell, S. Parsons, P.J. Sadler, Proc. Natl.
Acad. Sci. USA 102, 18269 (2005).
[6] H. Petzold, J. Xu, P.J Sadler, Angew Chem Int Ed Engl. 47, 3008 (2008).
[7] H. Petzold, P.J Sadler, Chem. Comm., DOI: 10.1039/b805358h (2008).
[8] S.J. Dougan, A. Habtemariam, S. McHale, S. Parsons, P.J. Sadler, (2008) in press.
[9] H.-K. Liu, S.J. Berners-Price, F. Wang, J.A. Parkinson, J. Xu, J. Bella, P.J. Sadler, Angew. Chem. Int. Ed.
45, 8153 (2006).
[10] T. Bugarcic, O. Nováková, A. Halámiková, L. Zerzánková, O. Vrána, J. Kašpárková, A. Habtemariam, S.
Parsons, P. J. Sadler, V. Brabec, submitted.
[11] A.F.A. Peacock, S. Parsons, P.J. Sadler, J. Am. Chem. Soc. 129, 3348 (2007).
[12] H. Kostrhunova, J. Florian, O. Novakova, A.F.P. Peacock, P.J. Sadler, V. Brabec, J. Med. Chem. (2008) in
press.
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