Mechanistic scrutiny of the oxidations of thiol‐containing drugs cysteamine and d‐penicillamine by cis‐diamminetetrachloroplatinum(IV)

Abstract

Cysteamine (CA) and d-penicillamine (Pen) are the thiol-containing drugs and good antioxidants. Their reactions with a cisplatin Pt(IV) prodrug cisdiamminetetrachloroplatinum(IV) (cis-[Pt(NH 3) 2 Cl 4 ]) were investigated by use of rapid scan, stopped-flow, and mass spectral techniques. The kinetic traces are biphasic in nature, encompassing a faster reduction of cis-[Pt(NH 3) 2 Cl 4 ] to cisplatin followed by slow substitutions on cisplatin. The reduction reactions were demonstrated to follow overall second-order kinetics over a wide pH range. The observed second-order rate constants versus pH profiles were established at 25.0 • C and 1.0 M ionic strength, indicating a huge increase of reaction rate with the increase of pH. However, the oxidations of CA and Pen by cis-[Pt(NH 3) 2 Cl 4 ] displayed different reaction stoichiometric ratios as revealed by the spectrophotometric titration experiments. Accordingly, CA was oxidized to CA-disulfide while Pen-sulfinic acid and Pen-disulfide were identified as the major products in the case of Pen via mass spectral analysis. The above similarities and differences are rationalized in terms of the proposed reaction mechanisms, which encompass similar rate-determining reactions for both CA and Pen, but involve disparate and faster followed-up reactions. Rate constants of the rate determining were derived at 25.0 • C and 1.0 M ionic strength. A consequent species reactivity analysis revealed that the species-SCH 2 CH 2 NH 3 + of CA and the species + H 3 NCH(COO-)CMe 2 Sof Pen played a predominant role toward the reduction of cis-[Pt(NH 3) 2 Cl 4 ] from pH 5 to 8, which also is a critical pH region for most of drugs.