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Catalytic organometallic anticancer complexes
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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 ISSN 0027-8424.
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Official URL: http://dx.doi.org/10.1073/pnas.0800076105
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 | ||||
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Subjects: | Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology |
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Divisions: | Faculty of Science, Engineering and Medicine > 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: |
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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. |
Data sourced from Thomson Reuters' Web of Knowledge
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