Reductions of the cisplatin-based platinum(IV) prodrug cis,cis,trans-[Pt(NH3)2Cl2Br2] by predominant biological thiols: kinetic and mechanistic studies

Abstract

The reductions of the anticancer-active platinum(IV) complex cis,cis,trans-[Pt(NH3)2Cl2Br2] by three predominant biological thiols (cysteine, homocysteine and glutathione) were studied kinetically in the present work. The reductions show second-order kinetics, being first order each in [Pt(IV)] and in [thiol]. The second-order rate constant k′ was increased dramatically when the pH of reaction media was increased. Thiols were oxidized to their intermolecular disulfides. Accordingly, mechanisms containing a transition state S-Br-Pt are proposed, from which the overall rate laws were deduced. The rate-determining rate constants were also calculated by simulation of k′-pH data. The reactivity trend for the reduction of cis,cis,trans-[Pt(NH3)2Cl2Br2] is ordered as Cys\u2009>\u2009GSH\u2009>\u2009Hcy by comparison of k′ under the same reaction conditions. The rate for the reduction of the axial bromide-coordinated Pt(IV) complex is much faster than that of reduction of the axial chloride-coordinated one. In addition, the reduction rate is related to the equatorial and axial ligands.