Disulfide-based 2-pyridyl-hydrazone prochelators induce iron deprivation and oxidative stress in ovarian cancer cells
Alterations of iron homeostasis are characteristic of malignant behavior and have been associated with poor prognosis in ovarian cancer patients. Iron-binding chelators are currently under investigation as potential cancer therapeutics because they allow manipulation of iron availability and redox chemistry. In addition, the design of prochelator systems enables the release of iron-binding chelators upon cell entry and therefore the sequestration of intracellular (rather than systemic) iron. We report the synthesis and biological evaluation of disulfide-based prochelators featuring a 2-pyridyl-hydrazone motif and resulting in a tridentate (S,N,N) donor set as found in several antiproliferative chelators (e.g., Triapine, Dp44mT, DpC, COTI-2). Upon disulfide reduction and iron(II) coordination, the chelators stabilize ferric complexes that are redox-active in neutral aqueous conditions. Symmetric prochelator (PH3-S)