Thiol-activated anticancer agents: The state of the art

Daniele Dalzoppo, Veronica Di Paolo, Laura Calderan, Gianfranco Pasut, Antonio Rosato, Anna Maria Caccuri, Luigi Quintieri

Research output: Contribution to journalReview articlepeer-review


The thiol or sulfhydryl group, as part of low molecular weight non-peptide biomolecules, as well as part of the cysteine residues in peptides and proteins, is known to play extremely important roles in several aspects of cellular function. Glutathione (γ-Glu-Cys-Gly; GSH) is the most abundant thiol-containing peptide in mammals, being present intracellularly in the low millimolar concentration range, but only in the low micromolar concentration range in the majority of extracellular fluids. Notably, intracellular levels of GSH have been found to be significantly upregulated in a number of human cancers, a phenomenon thought to contribute, in concert with overexpression of some GSHassociated enzymes, to the development of tumor cell chemo- and radioresistance. On the other hand, various natural and synthetic chemical entities of different sizes show significant cytotoxic activity only upon interaction with a thiol, and can therefore exploit the GSH-rich intracellular environment of tumors. This review article attempts to summarize the current structural and pharmacological knowledge in the field of thiol-activated anticancer agents, with a focus on the mechanism(s) of their activation. Even though a great part of the available thiol-activated anticancer compounds is still in the preclinical phase of testing, some of them are undergoing trials in cancer patients.

Original languageEnglish
Pages (from-to)4-20
Number of pages17
JournalAnti-Cancer Agents in Medicinal Chemistry
Issue number1
Publication statusPublished - Jan 1 2017


  • Cancer
  • Chemotherapy
  • Drug targeting
  • Glutathione
  • Thiol-mediated prodrug activation
  • Thiols

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Cancer Research


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