Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

ABSTRACT 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(NH3)2Cl4] and a carboplatin prodrug cis,trans‐[Pt(cbdca)(NH3)2Cl2] 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 Δ[Pt(IV)]:Δ[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 of the rate‐determining steps have been derived, indicating that the two prodrugs are reduced with a very similar rate in spite of the difference between the coordination ligands in their equatorial positions. The reactivity analysis in the case of cis,trans‐[Pt(cbdca)(NH3)2Cl2] unravels that one species of Hcy (form III) is almost exclusively responsible for the reductions at the physiological pH (7.4), although it is existing only 5.2% of the total Hcy. On the other hand, the dominant existing form II of Hcy virtually does not make a contribution to the overall reactivity at pH 7.4.