title: Thiol-Activated Anticancer Agents: The State of the Art.
abstract: 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.
authors.forename: Daniele
authors.initials: D
authors.lastname: Dalzoppo
authors.forename: Veronica
authors.initials: V
authors.lastname: Di Paolo
authors.forename: Laura
authors.initials: L
authors.lastname: Calderan
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pasut
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, I-00133, Rome, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Caccuri
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Largo Meneghetti 2, I-35131 Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Quintieri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D055808:Drug Discovery; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D005978:Glutathione