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

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

doi:10.1016/j.bmcl.2016.07.046

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

Jingran Dong, Shuying Huo, Shigang Shen, Jianzhong Xu, Tiesheng Shi, Lars Ivar Elding

Hebei University

Research output: Contribution to journal › Article › peer-review

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 1.0 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.

Original language	English
Pages (from-to)	4261-4266
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2016.07.046
Publication status	Published - 2016 Sept 1

Subject classification (UKÄ)

Other Basic Medicine
Inorganic Chemistry

Free keywords

Anticancer
Glutathione
Kinetic analysis
Ormaplatin
Reduction
Tetrapaltin

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10.1016/j.bmcl.2016.07.046

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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 1.0 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.",

keywords = "Anticancer, Glutathione, Kinetic analysis, Ormaplatin , Reduction, Tetrapaltin",

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AU - Dong, Jingran

AU - Huo, Shuying

AU - Shen, Shigang

AU - Xu, Jianzhong

AU - Shi, Tiesheng

AU - Elding, Lars Ivar

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

KW - Anticancer

KW - Glutathione

KW - Kinetic analysis

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KW - Reduction

KW - Tetrapaltin

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

Abstract

Subject classification (UKÄ)

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