Intracellular nucleophilic thiols

Intracellular nucleophilic thiols, encompassing both low-molecular-weight species like glutathione (GSH) and macromolecular protein-bound cysteine residues, serve as the primary chemical targets for hypoxia-activated prodrugs (HAPs) and hypoxia-specific imaging markers (Raleigh et al., 1987). In the oxygen-depleted environment of solid tumors, these thiols act as traps for reactive drug intermediates generated through bioreductive metabolism. Specifically, nitroimidazole-based compounds and other bioreductive agents are reduced by intracellular enzymes, such as cytochrome P450 oxidoreductase, into highly reactive electrophilic species that subsequently form stable covalent adducts with the sulfur atoms of these thiols (Brown & Wilson, 2004). This selective accumulation in hypoxic cells allows for the targeted delivery of cytotoxic effects or the visualization of tumor hypoxia, which is a key driver of radioresistance and metastatic progression (Wilson & Hay, 2011). Consequently, the abundance and reactivity of these thiols are fundamental to the efficacy of hypoxia-targeted therapies and the accuracy of diagnostic hypoxia probes like pimonidazole (PubChem CID 124886).

Other names

GlutathioneProtein thiolsCysteine residuesHypoxic cell nucleophilesBioreductive adduct targetsNon-protein thiols

Bioreductive activation followed by covalent conjugation to nucleophilic thiol groups (Raleigh et al., 1987; Brown & Wilson, 2004).