May 14, 2010
Oxidative Addition of Singlet Oxygen to Pt (II) Thiolato Complex: A Model System for Oxidation of cis-Platinum Antitumor Drugs
MBRS RISE MS-to-PhD Scholar Lori Tallorin*, Linda Ye*, Dong Zhang*, and Matthias Selke *Department of Chemistry and Biochemistry,
California State University Los Angeles, Los Angeles, California 90032-4226 Keywords: Photooxidation; Persulfoxide; Metal Thiolate; Singlet Oxygen; Peroxide Effective treatment of nephrotoxicity by recognized cis- platinum antitumor drugs requires a mechanistic understanding of how these drugs initiate toxicity upon binding to cysteine-rich residues of metallothionein (MTs), a protein that is predominant in liver and kidneys and responsible for the detoxification of heavy metals. A study by Saryan et al. (1992) has shown that binding to cysteine-rich residues on MTs is cis-Pt(II) dependent implying that these Pt(II) cysteinato complexes are mainly responsible for nephrotoxicity. The exact mechanism of how these antitumor drugs induce toxicity is unclear. It is believed that oxidation of these metal bound MT cysteine residues may be one of the processes leading to severe side effects of cis-platinum drugs. The goal of this study is to determine whether short- lived peroxidic intermediate(s) are causing some of the damage. Studies by Gray et al. (1997) indicate the formation of the sulfinite product implying an intramolecular oxygen atom transfer upon photooxidation of a Pt(II) thiolate complex, implying intramolecular oxidation and no intermolecular oxygen atom transfer by the peroxidic intermediate. However, studies currently being conducted by our group indicate that peroxidic intermediates involved in the oxidation of the Pt-S-cys motif are in fact capable of intermolecular oxygen atom transfer and may therefore be involved in oxidative damage. The mechanisms of the peroxidic intermediate(s) produced by these Pt (II) cysteinato complexes may provide clues to understanding the mechanistic intricacies involved in the nephrotoxicity of these cis- platinum drugs.