Kinetics and mechanism for reduction of anticancer-active tetrachloroam(m)ine platinum(IV) compounds by glutathione

Glutathione (GSH) reduction of the anticancer-active platinum(IV) compounds trans-[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4( cha)(NH3)] (3) (cha = cyclohexylamine), and cis-[PtCl4(NH3)(2)] (4) has bee n investigated at 25 degrees C in a 1.0 M aqueous medium at pH 2.0-5.0 (1) and 4.5-6.8 (2-4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law d[Pt(IV)]/dt=k[GSH](tot)[Pt(IV)], where k is a pH-dependent rate constant and [GSH](tot) the total concentration of glutathione. The reduction takes place via parallel reactions between the p latinum(IV) complexes and the various protolytic species of glutathione. Th e pH dependence of the redox kinetics is ascribed to displacement of these protolytic equilibria. The thiolate species GS(-) is the major reductant un der the reaction conditions used. The second-order rate constants for reduc tion of compounds 1-4 by GS(-) are (1.43 +/- 0.01) x 10(7), (3.86 +/- 0.03) x 10(6), (1.83 +/- 0.01) x 10(6), and (1.18 +/- 0.01) x 10(6) M-1 s(-1), r espectively. Rate constants for reduction of 1 by the protonated species GS H are more than five orders of magnitude smaller. The mechanism for the red uctive elimination reactions of the Pt(IV) compounds is proposed to involve an attack by glutathione on one of the mutually trans coordinated chloride ligands, leading to two-electron transfer via a chloride-bridged activated complex. The kinetics results together with literature data indicate that platinum(IV) complexes with a trans Cl-Pt-Cl axis are reduced rapidly by gl utathione as well as by ascorbate. In agreement with this observation, cyto toxicity profiles for such complexes are very similar to those for the corr esponding platinum(II) product complexes. The rapid reduction within Is of the platinum(IV) compounds with a trans Cl-Pt-Cl axis to their platinum(II) analogs does not seem to support the strategy of using kinetic inertness a s a parameter to increase anticancer activity, at least for this class of c ompounds.