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.

The electro‐oxidation of formamidine disulfide, an important sulfur‐containing compound, was simultaneously investigated with on‐line high‐performance liquid chromatography and cyclic voltammetry. Using a home‐made microporous sampler located at the electrode interface, the solution on the electrode surface was in situ sampled and analyzed. The electrochemical scanning was synchronously performed, which allowed the electro‐oxidation products to be detected at a given potential. The main products on the surface of platinum electrode were found to be thiourea, formamidine sulfinic acid, cyanamide, and elemental sulfur. Forced convection arising from the sampling played an important role in the electrochemical oxidation. The extraction of electrode surface solution promoted the renewal of reactant and its intermediates, which induced the change of cyclic voltammetry curve. The forced convection also contributed to the redox peak current of the species on the cyclic voltammetry curves through the change of concentration of reactant and its intermediates. This technique can help to explore the reaction mechanism of complex electrochemical reactions.