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)₂ and glucose conjugate G6PH3 have antiproliferative, pro-apoptotic effects in A2780 ovarian carcinoma cells. Both compounds sequester intracellular iron and impact the expression of the transferrin receptor TfR1 and the iron storage protein ferritin. Oxidative stress is found to be a component of the mechanism of action of these prochelators. Accordingly, the preformed iron complex FePH3 also leads to apoptosis and iron dysregulation, and its toxicity is enhanced when the antioxidant capacity of the cells is impaired. The incorporation of the 2-pyridyl-hydrazone motif in disulfide-based prochelators therefore combines iron sequestration with pro-oxidant effects that could enhance the pharmacological profile of this chelation approach for cancer applications.