Reduction of an asymmetric Pt(IV) prodrug fac-[Pt(dach)Cl3(OC(=O)CH3)] by biological thiol compounds: kinetic and mechanistic characterizations

An asymmetric Pt(IV) prodrug fac-[Pt (dach)Cl3(OC(=O)CH3)] (dach = 1,2-diaminocyclohexane) was synthesized, and the reduction of the Pt(IV) prodrug by three biological thiols glutathione (GSH), cysteine (Cys) and homocysteine (Hcy) was investigated by a stopped-flow spectrometer. All the reductions were followed by an overall second-order reaction with first-order in both [Pt(IV)] and [thiol]. The reduction of the Pt(IV) prodrug occurred through a chloride bridge (Pt-Cl-S) mediated two electron transfer process. Therefore, the coordinated chloride possesses a better bridging effect than the oxygen atom from the coordinated –CH3COO− of the Pt(IV) prodrug. A reactivity trend of k′Cys > k′GSH > k′Hcy is found, illustrating that the reactivity is followed by the trend of Cys > GSH > Hcy in pH 7.4 buffer. Transition state is formed between the axially coordinated chloride of the platinum(IV) complex and the sulfur atom from the thiol/thiolate group of Cys/Hcy/GSH.