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Review
. 2022 Dec:71:102213.
doi: 10.1016/j.cbpa.2022.102213. Epub 2022 Oct 4.

Taming glutathione potentiates metallodrug action

Hieu D Nguyen  1 , Loi H Do  2
Affiliations
Review

Taming glutathione potentiates metallodrug action

Hieu D Nguyen et al. Curr Opin Chem Biol. 2022 Dec.

Abstract

Metallodrugs that are redox sensitive or have labile coordination sites are particularly susceptible to inhibition by glutathione (GSH) and other endogenous thiols. Because GSH is an essential antioxidant, strategies to prevent thiol deactivation must consider their potential effects on normal cellular functions. In this short review, we describe general approaches for taming glutathione in metallodrug therapy and discuss their strengths and limitations. We also offer our perspectives on developing practical solutions that are effective and clinically relevant.

Keywords: Drug resistance; Glutathione; Metallodrugs; Metals in medicine; Toxicity.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
A) Comparison of the DMSO exchange rate constants (kDMSO) and IC50 values of untethered and tethered Ir(III) complexes. B) Studies of azide-alkyne cycloaddition reactions using dicopper(II) cryptands. C) Studies of azide-alkyne cycloaddition reactions using copper(II) hemicryptophane.
Scheme 1.
Scheme 1.
Structure of glutathione (GSH) and its effects on metallodrug therapy (left). Strategies to overcome GSH interference (right).
Scheme 2.
Scheme 2.
A) GSH can react with neutral and cationic electrophiles to form covalent adducts. The electrophilicity values (E) of representative thiol scavengers are shown. B) Development of copper complexes that reduce intracellular GSH concentrations as well as generate reactive oxygen species to kill cancer cells.
Scheme 3.
Scheme 3.
A) A proposed mechanistic cycle for catalytically depletion of GSH and generation of superoxide radicals by Ir1. B) Activation of gold(III) pincer complexes with light to generate bioacative gold(I) bis(thiolate) species.
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