An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols

Ka Chung Tong, Chun Nam Lok, Pui Ki Wan, Di Hu, Yi Man Eva Fung, Xiao Yong Chang, Song Huang, Haibocc Jiang, Chi Ming Che

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M-S bond formation, AuMesoIX is unique in that the mesocarbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols. AuMesoIX was shown to modify reactive cysteine residues and inhibit the activities of anticancer protein targets including thioredoxin, peroxiredoxin, and deubiquitinases. Treatment of cancer cells with AuMesoIX resulted in the formation of gold-bound sulfur-rich protein aggregates, oxidative stress-mediated cytotoxicity, and accumulation of ubiquitinated proteins. Importantly, AuMesoIX exhibited effective antitumor activity in mice. Our study has uncovered a gold(III)-induced ligand scaffold reactivity for thiol targeting that can be exploited for anticancer applications.

Original languageEnglish
Pages (from-to)1321-1329
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number3
DOIs
Publication statusPublished - 21 Jan 2020

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