Inhibition of Cancer Cell Growth by Ruthenium(II) Arene Complexes

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-ethylethyle...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 44; no. 22; pp. 3616 - 3621
Main Authors:	Morris, Robert E, Aird, Rhona E, del Socorro Murdoch, Piedad, Chen, Haimei, Cummings, Jeff, Hughes, Nathan D, Parsons, Simon, Parkin, Andrew, Boyd, Gary, Jodrell, Duncan I, Sadler, Peter J
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 25-10-2001
Subjects:	Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Crystallography, X-Ray DNA Adducts - chemistry Drug Screening Assays, Antitumor Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General aspects Humans Medical sciences Molecular Structure Oligonucleotides - chemistry Organometallic Compounds - chemical synthesis Organometallic Compounds - chemistry Organometallic Compounds - pharmacology Pharmacology. Drug treatments Ruthenium Structure-Activity Relationship Topoisomerase I Inhibitors Topoisomerase II Inhibitors Tumor Cells, Cultured Antineoplastic agent Cationic complex Divalent metal Complexes Molecular structure Cytotoxicity Ovary Structure activity relation Cymene Complexes Mixed Biphenyl Chloro complex Iodo complex Mechanism of action Chemical synthesis Tumor cell Ruthenium II Complexes Human Arene Organic ligand Transition metal Complexes X ray diffraction In vitro Cell line Benzene Platinoid Complexes Hapto complex Crystalline structure
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Summary:	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.
Bibliography:	ark:/67375/TPS-5S8WBXNB-0 istex:A0BE2FA6DE0378495FAF6C73FEB11797A6583733 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm010051m