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

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 1.0 M 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