Kinetics and Mechanism for Reduction of trans-Dichlorotetracyanoplatinate(IV) by Thioglycolic Acid, l-Cysteine, dl-Penicillamine, and Glutathione in Aqueous Solution

Abstract

SynopsisVarious protolytic species of thiols RSH (thioglycolic acid, l-cysteine, dl-penicillamine, and glutathione) in rapid equilibria with each other reduce trans-[Pt(CN)4Cl2]2- in parallel, halide-bridged electron transfer reactions. A linear Bronsted correlation between the reactivity of the thiolate anions RS- and their basicity is observed. The mechanism derived might be used as a model for reduction of Pt(IV) antitumor drugs by thiol-containing molecules before their interaction with DNA.AbstractReduction of trans-[Pt(CN)4Cl2]2- (as a model compound for antitumor-active platinum(IV) complexes) by thiols, RSH (thioglycolic acid, l-cysteine, dl-penicillamine, and glutathione), has been studied in a 1.00 M aqueous perchlorate medium by use of stopped-flow spectrophotometry at 25 °C in the interval 7.08 × 10-6 ≤ [H+] ≤ 1.00 M. Time-resolved spectra show that redox takes place directly without initial substitution at Pt(IV). The stoichiometry is [RSH]:[Pt(IV)] = 2:1. Reduction is first-order with respect to [Pt(IV)] and the total concentration of thiol [RSH]tot. The bromide complex trans-[Pt(CN)4Br2]2- is reduced 47 times faster than trans-[Pt(CN)4Cl2]2- by cysteine. The [H+]-dependence of the observed kinetics can be rationalized by a reaction mechanism in which the platinum(IV) complex is reduced in parallel reactions by the various protolytic species present in rapid equilibria with each other, via halide-bridged electron transfer. Second-order rate constants for a particular reductant derived from the pH-dependence of the overall kinetics increase several orders of magnitude when the molecular forms of the reductants are deprotonated. For instance, no reduction of platinum(IV) by the fully protonated cation of glutathione can be observed, whereas the various deprotonated forms reduce the complex with second-order rate constants of 23.4 ± 0.3, 655 ± 4, and (1.10 ± 0.01) × 108 M-1 s-1, respectively. Thiolate anions reduce the platinum(IV) complex (1.7−19) × 105 times faster than the corresponding vicinal thiol forms. The second-order rate constants kRS− for reaction of thiolate anions RS- with [Pt(CN)4Cl2]2- are described by the Bronsted correlation log kRS− = (0.82 ± 0.08)pKRSH + (1.1 ± 0.7). The slope of 0.82 indicates that the basicity of RS- is a predominant factor in determining the reactivity toward the Pt(IV) complex. Reduction of Pt(IV) antitumor drugs by thiol-containing molecules before interaction between Pt(II) and DNA may take place via similar reaction mechanisms. (Less)