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An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols.
Tong, Ka-Chung; Lok, Chun-Nam; Wan, Pui-Ki; Hu, Di; Fung, Yi Man Eva; Chang, Xiao-Yong; Huang, Song; Jiang, Haibo; Che, Chi-Ming.
Afiliação
  • Tong KC; State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China.
  • Lok CN; Laboratory for Synthetic Chemistry and Chemical Biology, Health@InnoHK, Hong Kong, China.
  • Wan PK; State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China.
  • Hu D; Laboratory for Synthetic Chemistry and Chemical Biology, Health@InnoHK, Hong Kong, China.
  • Fung YME; State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China.
  • Chang XY; Laboratory for Synthetic Chemistry and Chemical Biology, Health@InnoHK, Hong Kong, China.
  • Huang S; State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China.
  • Jiang H; Laboratory for Synthetic Chemistry and Chemical Biology, Health@InnoHK, Hong Kong, China.
  • Che CM; State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China.
Proc Natl Acad Sci U S A ; 117(3): 1321-1329, 2020 01 21.
Article em En | MEDLINE | ID: mdl-31896586
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 meso-carbon 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Cisteína / Ouro / Mesoporfirinas / Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Cisteína / Ouro / Mesoporfirinas / Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article