Spectroscopic, kinetic, and theoretical analyses of oxidation of dl-ethionine by Pt(IV) anticancer model compounds

• Published in: Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy Molecular and biomolecular spectroscopy, 2019-12, Vol.223, p.117328, Article 117328
• Main Authors: Wang, Jinhu, Yao, Haiping, Lu, Taotao, Dong, Jingran, Xu, Benyan, Liu, Yang, Liu, Chunli, Zhou, Li, Shi, Tiesheng
• Format: Article
• Language: English
• Subjects: Ethionine; Kinetic analysis; Pt(IV) complex; QM/MM calculations; Spectroscopy
• ISSN: 1386-1425
• DOI: 10.1016/j.saa.2019.117328

Ethionine is an S-ethyl analog of methionine (Met) having a small change in structure. But it is a chemical carcinogen and an antagonist of Met, thus displaying a disparate biological profile. The oxidations of ethionine by biologically important oxidants have not been exploited. Oxidations of dl-ethionine by Pt(IV) anticancer model complexes trans-[PtX2(CN4)]2− (X = Cl or Br) were thus analyzed by time-resolved and stopped-flow spectral techniques. Overall second-order kinetics was established, being first-order in [Pt(IV)] and [Ethionine]tot (the total concentration of ethionine); the observed second-order rate constant k' versus pH profiles were obtained. A stoichiometry of Δ[Pt(IV)]:Δ[Ethionine]tot = 1:1 was unraveled, indicating that ethionine was oxidized to ethionine-sulfoxide which was confirmed by NMR spectroscopic and high-resolution mass spectral analyses. In the proposed reaction mechanism which is similar to that for the oxidation of Met by the same Pt(IV) compounds, the rate-determining steps are rationalized in terms of a bridge formation between one of the coordinated halides in [PtX2(CN4)]2− and the sulfur atom in ethionine, followed by an X+ transfer. Moreover, a large rate enhancement for the reaction of ethionine with [PtBr2(CN4)]2− compared with [PtCl2(CN4)]2− strongly supports an X+ transfer mechanism. Furthermore, a combined quantum-mechanical/molecular-mechanical (QM/MM) method was utilized to simulate a Cl+ transfer mechanism from trans-[PtCl2(CN)4]2− to ethionine. The simulations unraveled the energetically stable structures of reactants and products, which favor the Cl+ transfer process. Rate constants of the rate-determining steps have been derived. Ratios of k (ethionine)/k (Met) are between 2.2 and 2.6 obtained for the three protolytic species of ethionine and Met; the enhanced reactivity might be partially responsible for the disparate biological profiles. The kinetics and mechanism of oxidation of ethionine by Pt(IV) complexes have been characterized by stopped-flow, time-resolved, NMR and mass spectral techniques. [Display omitted] •Ethionine, an S-ethyl analog of methionine, is toxic and a carcinogen.•Oxidation of ethionine by Pt(IV) anticancer model compounds was analyzed.•Stopped-flow and time-resolved spectral techniques were used for kinetic study.•High-resolution NMR and ESI spectra confirm the oxidation product of ethionine.•Theoretical calculations support the proposed reaction mechanism.