Kinetics and mechanism for reduction of Pt(IV) anticancer model compounds by Se-methyl L-selenocysteine. Comparison with L-selenomethionine

Se-methyl L-selenocysteine (MeSeCys) is one of the major organic selenium compounds acquired from the diet by human beings. It has been shown to have anticancer activity and cancer prevention functions. However, its antioxidant activity, largely related to its biological function, has not been well characterized so far. We here report a stopped-flow kinetic study of the reduction of the Pt(IV) anticancer model compounds trans-[PtX2(CN)4]2− (X = Cl; Br) by MeSeCys in a wide pH range. Overall second-order kinetics is established for the redox reactions, and spectrophotometric titrations indicate a 1:1 reaction stoichiometry. The MeSeCys is oxidized to its selenoxide form, as identified by high-resolution mass spectra. The proposed reaction mechanism involves parallel attack on one of the trans-coordinated halides of the Pt(IV) complexes by the selenium atom of the various MeSeCys protolytic species. Rate constants for the rate determining steps as well as the pKa values of the various protolytic species of MeSeCys have been determined at 25.0 °C and 1.0 M ionic strength. A bridged two-electron transfer mechanism for the rate-determining steps is supported by rapid-scan spectra, activation parameters, and by the much larger reaction rate of [PtBr2(CN)4]2− compared to [PtCl2(CN)4]2−. The experiments indicate that the reduction of [PtX2(CN)4]2− by MeSeCys proceeds via a similar reaction mechanism as L-selenomethionine (SeMet) studied previously. However, there is a large reactivity difference between these two selenium compounds, as a matter of fact the largest one observed so far when compared to other redox systems. It differs between the various protolytic species of MeSeCys and SeMet. The different reactivity of MeSeCys and SeMet in the reduction of various biologically relevant oxidants might account for their disparate efficacies as anticancer agents.