Pt(IV) anticancer active complexes are commonly regarded as prodrugs, and the reduction of the prodrugs to their Pt(II) analogs is the activation process. The reduction of a cisplatin prodrug cis-[Pt(NH 3 ) 2 Cl 4 ] and a carboplatin prodrug cis,trans-[Pt(cbdca)(NH 3 ) 2 Cl 2 ] by DL-homocysteine (Hcy) has been investigated kinetically in a wide pH range in this work. The reduction process follows overall second-order kinetics: −d[Pt(IV)]/dt = k [Hcy] tot [Pt(IV)], where [Hcy] tot stands for the total concentration of Hcy and k pertains to the observed second-order rate constants. The k versus pH profiles have been established for both prodrugs. Spectrohotometric titrations reveal a stoichiometry of [Pt(IV)]: [Hcy] tot = 1:2; homocystine is identified as the major oxidation product of Hcy by high-resolution mass spectrometry. A reaction mechanism has been proposed, which involves all the four protolysis species of Hcy attacking the Pt(IV) prodrugs in parallel. Moreover, these parallel attacks are the rate-determining steps, resulting in a Cl + transfer from the Pt(IV) prodrugs to the attacking sulfur atom. Rate constants An Accumet Basic AB15 Plus pH meter, equipped with an Accumet AccutupH R combination pH electrode (Fisher Scientific, Pittsburgh, PA), was used to measure the pH values of buffer solutions. Each time, the electrode was calibrated using the standard buffers

The development of Pt(IV) anticancer prodrugs to overcome the detrimental side effects of Pt(II)-based anticancer drugs is of current interest. The kinetics and reaction mechanisms of the reductive activation of the carboplatin Pt(IV) prodrug cis,trans-[Pt(cbdca)(NH3)2Cl2] (cbdca = cyclobutane-1,1-dicarboxylate) by the major small-molecule reductants in human plasma were analyzed in this work. The reductants included ascorbate (Asc), the thiol-containing molecules L-cysteine (Cys), DL-homocysteine (Hcy), and glutathione (GSH), and the dipeptide Cys–Gly. Overall second-order kinetics were established in all cases. At the physiological pH of 7.4, the observed second-order rate constants k′ followed the order Asc << Cys–Gly ~ Hcy < GSH < Cys. This reactivity order together with the abundances of the reductants in human plasma indicated Cys as the major small-molecule reductant in vivo, followed by GSH and ascorbate, whereas Hcy is much less important. In the cases of Cys and GSH, detailed reaction mechanisms and the reactivity of the various protolytic species at physiological pH were derived. The rate constants of the rate-determining steps were evaluated, allowing the construction of reactivity-versus-pH distribution diagrams for Cys and GSH. The diagrams unraveled that species III of Cys (−SCH2CH(NH3+)COO−) and species IV of GSH (−OOCCH(NH3+)CH2CH2CONHCH(CH2S−)- CONHCH2COO−) were exclusively dominant in the reduction process. These two species are anticipated to be of pivotal importance in the reduction of other types of Pt(IV) prodrugs as well.

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-[PtX 2 (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 pK a values of the various protolytic species of MeSeCys have been determined at 25.0°C and 1.0 M ionic strength. A bridged twoelectron transfer mechanism for the rate-determining steps is supported by rapid-scan spectra, activation parameters, and by the much larger reaction rate of [PtBr 2 (CN) 4 ] 2− compared to [PtCl 2 (CN) 4 ] 2− . The experiments indicate that the reduction of [PtX 2 (CN) 4 ] 2− by MeSeCys proceeds via a similar reaction mechanism as Lselenomethionine (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.

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