Kinetics and mechanism of reactions of the drug tiopronin with platinum(IV) complexes

• Published in: Journal of inorganic biochemistry Vol. 125; pp. 9 - 15
• Main Authors: Huo, Shuying, Shi, Hongmei, Liu, Dongzhi, Shen, Shigang, Zhang, Jiong, Song, Changying, Shi, Tiesheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2013
• Subjects: Cisplatin - chemistry; Hydrogen-Ion Concentration; Kinetics; Mass Spectrometry; Mechanism; Organoplatinum Compounds - chemistry; Oxidation kinetics; Oxidation-Reduction; Prodrugs - chemistry; Pt(IV) complex; Tiopronin; Tiopronin - chemistry; Oxidation kinetics; Tiopronin; Pt(IV) complex; Mechanism
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2013.04.003

Tiopronin, a synthetic thiol-containing drug being used in treatments of cystinuria and certain types of rare arthritis, is also a hepatoprotective and a detoxifying agent. Many analytical methods have been developed based on its redox chemistry with metal ions/complexes, but the kinetic and mechanistic aspects are poorly understood. In this work, the oxidation of tiopronin by cisplatin prodrug and a model compound, cis-[Pt(NH3)2Cl4] and trans-[PtCl2(CN)4]2−, was investigated. The oxidation kinetics was followed by a stopped-flow spectrophotometer over a wide pH range under the pseudo first-order conditions of [Tiopronin]≫[Pt(IV)]. Time-resolved spectra were also recorded for both Pt(IV) complexes, enabling to establish an overall second-order rate law: −d[Pt(IV)]/dt=k′[Tiopronin][Pt(IV)], where k′ pertains to observed second-order rate constants. Under the kinetic conditions, tiopronin was oxidized to form the tiopronin-disulfide exclusively as identified by mass spectrometry. A reaction mechanism was proposed, involving parallel reductions of the Pt(IV) complexes by the three protolytic tiopronin species as rate-determining steps. The rate constants for the rate-determining steps were derived. The fully deprotonated tiopronin is about 4×104 more reactive than its corresponding thiol form for both Pt(IV) complexes; the huge reactivity difference orchestrates closely with the fact that the nucleophilicity of thiolate is much higher than the corresponding thiol. Hence, the attack of the sulfur atom in thiol/thiolate of tiopronin on the axially-coordinated chloride in the Pt(IV) complexes is nucleophilic in nature in the rate-determining steps, resulting in a bridge formation and a subsequent bridged electron-transfer.
Second-order rate constants k′ as a function of pH at 25.0°C and ionic strength of 1.0M for oxidation of tiopronin by cis-[Pt(NH3)2Cl4] and trans-[PtCl2(CN)4]2− (data points were obtained). The solid curve was obtained by fitting Eq. (6) the experimental data by use of a weighed nonlinear least-squares method. [Display omitted]
•The oxidation of tiopronin by cis-[Pt(NH3)2Cl4] and trans-[PtCl2(CN)4]2− was studied.•Tiopronin was oxidized to tiopronin disulfide exclusively.•A general rate law was established over a wide pH range.•A detailed reaction mechanism is proposed accordingly.