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Reduction of an asymmetric Pt(IV) prodrug fac-[Pt(dach)Cl3(OC(=O)CH3)] by biological thiol compounds: kinetic and mechanistic characterizations

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Abstract

An asymmetric Pt(IV) prodrug fac-[Pt (dach)Cl3(OC(=O)CH3)] (dach = 1,2-diaminocyclohexane) was synthesized, and the reduction of the Pt(IV) prodrug by three biological thiols glutathione (GSH), cysteine (Cys) and homocysteine (Hcy) was investigated by a stopped-flow spectrometer. All the reductions were followed by an overall second-order reaction with first-order in both [Pt(IV)] and [thiol]. The reduction of the Pt(IV) prodrug occurred through a chloride bridge (Pt-Cl-S) mediated two electron transfer process. Therefore, the coordinated chloride possesses a better bridging effect than the oxygen atom from the coordinated –CH3COO− of the Pt(IV) prodrug. A reactivity trend of k′Cys > k′GSH > k′Hcy is found, illustrating that the reactivity is followed by the trend of Cys > GSH > Hcy in pH 7.4 buffer.

Graphical abstract

Transition state is formed between the axially coordinated chloride of the platinum(IV) complex and the sulfur atom from the thiol/thiolate group of Cys/Hcy/GSH.

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Acknowledgements

Financial support for this work through grants from the National Natural Science Foundation of China (21406047) and the Natural Science Foundation of Hebei Province (B2016201014) is gratefully acknowledged.

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Authors and Affiliations

  1. College of Chemistry and Environmental Science, Key Laboratory of Analytical Science and Technology of Hebei Province, and MOE Key Laboratory of Medicinal Chemistry and Molecular Diagnostics, Hebei University, Baoding, 071002, Hebei Province, People’s Republic of China

    Yafang Wang, Dongying Ma, Jingjing Sun, Changying Song & Shuying Huo

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  1. Yafang Wang
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Wang, Y., Ma, D., Sun, J. et al. Reduction of an asymmetric Pt(IV) prodrug fac-[Pt(dach)Cl3(OC(=O)CH3)] by biological thiol compounds: kinetic and mechanistic characterizations. Transit Met Chem 46, 623–631 (2021). https://doi.org/10.1007/s11243-021-00480-6

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