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

Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1321-1329. doi: 10.1073/pnas.1915202117. Epub 2020 Jan 2.


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.

Keywords: antitumor agents; cysteine thiol conjugation; gold; ligand reactivity; porphyrin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Cysteine / chemistry*
  • Deubiquitinating Enzymes / chemistry
  • Deubiquitinating Enzymes / metabolism
  • Gold / chemistry*
  • HCT116 Cells
  • Humans
  • Mesoporphyrins / chemistry*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms, Experimental / drug therapy
  • Peroxiredoxins / chemistry
  • Peroxiredoxins / metabolism
  • Protein Binding
  • Thioredoxins / chemistry
  • Thioredoxins / metabolism
  • Tissue Distribution


  • Antineoplastic Agents
  • Mesoporphyrins
  • mesoporphyrin IX
  • Thioredoxins
  • Gold
  • Peroxiredoxins
  • Deubiquitinating Enzymes
  • Cysteine