Dougan, Sarah J., Habtemariam, Abraha, McHale, Sarah E., Parsons, S. (Simon) and Sadler, P. J. (2008) Catalytic organometallic anticancer complexes. Proceedings of the National Academy of Sciences of the United States of America, Vol.105 (No.33). pp. 11628-11633. doi:10.1073/pnas.0800076105

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Abstract

Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ligand and a sigma-donor/pi-acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich "piano-stool" ruthenium arene complexes [(eta(6)-arene)Ru(azpy)I](+) (where arene = p-cymene or biphenyl, and azpy = N,N-dimethylphenyl- or hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine Ru-II complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential -0.2 to -0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione (gamma-L-Glu-L-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Aromatic compounds, Cell-mediated cytotoxicity, Glutathione, Antineoplastic agents -- Development, Organometallic compounds
Journal or Publication Title:	Proceedings of the National Academy of Sciences of the United States of America
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Official Date:	19 August 2008
Dates:	Date Event 19 August 2008 Published
Volume:	Vol.105
Number:	No.33
Number of Pages:	6
Page Range:	pp. 11628-11633
DOI:	10.1073/pnas.0800076105
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Oncosense Ltd.

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