| Abstract
| - The reduction of the platinum(IV) prodrug trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2)(NH3)] (JM335) by l-cysteine,dl-penicillamine, dl-homocysteine, N-acetyl-l-cysteine, 2-mercaptopropanoic acid, 2-mercaptosuccinic acid, andglutathione has been investigated at 25 °C in a 1.0 M aqueous perchlorate medium with 6.8 ≤ pH ≤ 11.2 usingstopped-flow spectrophotometry. The stoichiometry of Pt(IV):thiol is 1:2, and the redox reactions follow thesecond-order rate law −d[Pt(IV)]/dt = k[Pt(IV)][RSH]tot, where k denotes the pH-dependent second-order rateconstant and [RSH]tot the total concentration of thiol. The pH dependence of k is ascribed to parallel reductionsof JM335 by the various protolytic species of the thiols, the relative contributions of which change with pH.Electron transfer from thiol (RSH) or thiolate (RS-) to JM335 is suggested to take place as a reductive eliminationprocess through an attack by sulfur at one of the mutually trans chloride ligands, yielding trans-[Pt(OH)2(c-C6H11NH2)(NH3)] and RSSR as the reaction products, as confirmed by 1H NMR. Second-order rate constantsfor the reduction of JM335 by the various protolytic species of the thiols span more than 3 orders of magnitude.Reduction with RS- is ∼30−2000 times faster than with RSH. The linear correlation log(kRS-) = (0.52 ± 0.06)pKRSH − (2.8 ± 0.5) is observed, where kRS- denotes the second-order rate constant for reduction of JM335 bya particular thiolate RS- and KRSH is the acid dissociation constant for the corresponding thiol RSH. The slopeof the linear correlation indicates that the reactivity of the various thiolate species is governed by their protonbasicity, and no significant steric effects are observed. The half-life for reduction of JM335 by 6 mM glutathione(40-fold excess) at physiologically relevant conditions of 37 °C and pH 7.30 is 23 s. This implies that JM335, inclinical use, is likely to undergo in vivo reduction by intracellular reducing agents such as glutathione prior tobinding to DNA. Reduction results in the immediate formation of a highly reactive platinum(II) species, i.e., thebishydroxo complex in rapid protolytic equilibrium with its aqua form.
- Reduction of the anticancer trans platinum(IV) prodrug JM335 by thiols in a moderately alkaline aqueous perchlorate medium is quite rapid and yields trans-[Pt(OH)2(c-C6H11NH2)(NH3)] as the reaction product. The mechanism of reduction involves reductive attack by thiol or thiolate on one of the mutually trans chloride ligands, leading to the formation of a chloride-bridged activated complex.
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