Inhibition of cancer cell growth by ruthenium(II) arene complexes

Robert E. Morris, Rhona E. Aird, Piedad del Socorro Murdoch, Haimei Chen, Jeffrey Cummings, Nathan D. Hughes, Simon Parsons, Andrew Parkin, Gary Boyd, Duncan I. Jodrell, Peter J. Sadler

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Abstract

Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(η6-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(η6-p-cymene)Ru(en)Cl]PF6 (5), [(η6-p-cymene)RuCl2(isonicotinamide)] (7), and [(η6-biphenyl)Ru(en)Cl]PF6 (9) are reported. They have “piano stool” geometries with η6 coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru−Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.
Original languageEnglish
Pages (from-to)3616-3621
Number of pages6
JournalJournal of Medicinal Chemistry
Volume44
DOIs
Publication statusPublished - 2001
Externally publishedYes

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    Morris, R. E., Aird, R. E., Murdoch, P. D. S., Chen, H., Cummings, J., Hughes, N. D., Parsons, S., Parkin, A., Boyd, G., Jodrell, D. I., & Sadler, P. J. (2001). Inhibition of cancer cell growth by ruthenium(II) arene complexes. Journal of Medicinal Chemistry, 44, 3616-3621. https://doi.org/10.1021/jm010051m