Catalytic organometallic anticancer complexes
- 19 August 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (33), 11628-11633
- https://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 σ-donor/π-acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich “piano-stool” ruthenium arene complexes [(η6-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 RuII 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 (γ-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.Keywords
This publication has 39 references indexed in Scilit:
- Non-irradiation-derived reactive oxygen species (ROS) and cancer: therapeutic implicationsAmino Acids, 2006
- Catalysis of regioselective reduction of NAD+ by ruthenium(II) arene complexes under biologically relevant conditionsJBIC Journal of Biological Inorganic Chemistry, 2006
- The emerging role of reactive oxygen species in cancer therapyEuropean Journal of Cancer, 2004
- Measuring reactive species and oxidative damagein vivoand in cell culture: how should you do it and what do the results mean?British Journal of Pharmacology, 2004
- Bioorganometallic Chemistry: Structural Diversity of Organometallic Complexes with Bioligands and Molecular Recognition Studies of Several Supramolecular Hosts with Biomolecules, Alkali-Metal Ions, and Organometallic PharmaceuticalsOrganometallics, 2003
- New Colorimetric Cytotoxicity Assay for Anticancer-Drug ScreeningJNCI Journal of the National Cancer Institute, 1990
- Chemistry of bipyridyl-like ligands. 3. Complexes of ruthenium(II) with 2-((4-nitrophenyl)azo)pyridineInorganic Chemistry, 1984
- Chemistry of ruthenium. 12. Reactions of bidentate ligands with diaquabis[2-(arylazo)pyridine]ruthenium(II) cation. Stereoretentive synthesis of tris chelates and their characterization: metal oxidation, ligand reduction, and spectroelectrochemical correlationInorganic Chemistry, 1983
- Chemistry of ruthenium. 7. Aqua complexes of isomeric bis[(2-arylazo)pyridine]ruthenium(II) moieties and their reactions: solvolysis, protic equilibriums, and electrochemistryInorganic Chemistry, 1983
- Glutathione. 6. Probable mechanism of action of diazene antibioticsJournal of Medicinal Chemistry, 1972