Reduction of trans-[Pt(CN)(4)Cl-2](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 degrees C in the interval 7.08 x 10(-6) less than or equal to [H+] less than or equal to 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)(4)Br-2](2-) is reduced 47 times faster than trans-[Pt(CN)(4)Cl-2](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) x 10(8) M(-1) s(-1), respectively. Thiolate anions reduce the platinum(IV) complex (1.7-19) x 10(5) times faster than the corresponding vicinal thiol forms. The second-order rate constants k(Rs-) for reaction of thiolate anions RS(-) with [Pt(CN)(4)Cl-2](2-) are described by the Bronsted correlation log k(RS-) = (0.82 +/- 0.08)pK(RSH) + (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.