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

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(NH 3 ) 2 Cl 4 ] and a carboplatin prodrug cis,trans ‐[Pt(cbdca)(NH 3 ) 2 Cl 2 ] 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)(NH 3 ) 2 Cl 2 ] 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.