Reactivity of the glutathione species towards the reduction of ormaplatin (or tetraplatin)

Jingran Dong; Shuying Huo; Shigang Shen; Jianzhong Xu; Tiesheng Shi; Lars I Elding

doi:10.1016/j.bmcl.2016.07.046

Reactivity of the glutathione species towards the reduction of ormaplatin (or tetraplatin)

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4261-6. doi: 10.1016/j.bmcl.2016.07.046. Epub 2016 Jul 21.

Authors

Jingran Dong¹, Shuying Huo¹, Shigang Shen¹, Jianzhong Xu¹, Tiesheng Shi², Lars I Elding³

Affiliations

¹ College of Chemistry and Environmental Science, and the MOE Key Laboratory of Medicinal Chemistry and Molecular Diagnostics, Hebei University, Baoding 071002, Hebei Province, People's Republic of China.
² College of Chemistry and Environmental Science, and the MOE Key Laboratory of Medicinal Chemistry and Molecular Diagnostics, Hebei University, Baoding 071002, Hebei Province, People's Republic of China. Electronic address: rock@hbu.edu.cn.
³ Center for Analysis and Synthesis, Department of Chemistry, Lund University, PO Box 124, SE 221 00 Lund, Sweden. Electronic address: lars_ivar.elding@chem.lu.se.

PMID: 27481559
DOI: 10.1016/j.bmcl.2016.07.046

Abstract

The reduction of ormaplatin (tetraplatin), a prototype for Pt(IV) anticancer prodrugs, by glutathione (GSH) was kinetically characterized over a wide pH range at 25.0°C and 1.0M ionic strength. The reduction follows overall second-order kinetics, giving rise to the oxidized glutathione as the oxidation product, which was identified by high-resolution mass spectrometry. The reaction mechanism put forward involves parallel attacks by all the GSH species on the Pt(IV) prodrug as rate-determining steps. All rate constants for the rate-determining steps have been derived for the first time, enabling the construction of the reactivity of GSH species versus their pH distribution diagram. The diagram clearly displays that only one out of the five GSH species is the mainly responsible for the reduction of ormaplatin at the physiological pH of 7.4.

Keywords: Anticancer; Glutathione; Kinetic analysis; Ormaplatin (tetraplatin); Reduction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Glutathione / chemistry*
Hydrogen-Ion Concentration
Kinetics
Mass Spectrometry
Organoplatinum Compounds / chemistry*
Osmolar Concentration
Oxidation-Reduction
Prodrugs / chemistry

Substances

Antineoplastic Agents
Organoplatinum Compounds
Prodrugs
Glutathione
ormaplatin