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

Abstract

Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(eta(6)-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 [(eta(6)-p-cymene)Ru(en)Cl]PF(6) (5), [(eta(6)-p-cymene)RuCl(2)(isonicotinamide)] (7), and [(eta(6)-biphenyl)Ru(en)Cl]PF(6) (9) are reported. They have "piano stool" geometries with eta(6) 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.

• Authors: R E Morris, R E Aird, P del S Murdoch, H Chen, J Cummings, N D Hughes, S Parsons, A Parkin, G Boyd, D I Jodrell, P J Sadler
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 44 Issue 22 Pg. 3616-21 (Oct 25 2001) ISSN: 0022-2623 [Print] United States
• PMID: 11606126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA Adducts
• Enzyme Inhibitors
• Oligonucleotides
• Organometallic Compounds
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Ruthenium

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Crystallography, X-Ray
• DNA Adducts (chemistry)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Structure
• Oligonucleotides (chemistry)
• Organometallic Compounds (chemical synthesis, chemistry, pharmacology)
• Ruthenium
• Structure-Activity Relationship
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured