Reductions of the cisplatin-based platinum(IV) prodrug cis,cis,trans-[Pt(NH3)2Cl2Br2] by predominant biological thiols: kinetic and mechanistic studies
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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 > GSH > Hcy 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.
We gratefully acknowledge the financial support of this work by the Natural Science Foundation of Hebei Province (B2016201014), by the Natural Science Foundation of Educational Commission of Hebei Province (ZD2016073) and by the National Natural Science Foundation of China (21406047).
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Conflict of interest
All authors declare that they have no conflict of interest in this work.
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