Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators.

ABSTRACT: Iron scavengers (chelators) offer therapeutic opportunities in anticancer drug design by targeting the increased demand for iron in cancer cells as compared to normal cells. Prochelation approaches are expected to avoid systemic iron depletion as chelators are liberated under specific intracellular conditions. In the strategy described herein, a disulfide linkage is employed as a redox-directed switch within the binding unit of an antiproliferative thiosemicarbazone prochelator, which is activated for iron coordination following reduction to the thiolate chelator. In glutathione redox buffer, this reduction event occurs at physiological concentrations and half-cell potentials. Consistent with concurrent reduction and activation, higher intracellular thiol concentrations increase cell susce

SUBMITTER: Akam EA 

PROVIDER: S-EPMC4188698 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature