Disulfide-masked iron prochelators: Effects on cell death, proliferation, and hemoglobin production.

The iron metabolism of malignant cells, which is altered to ensure higher acquisition and utilization, motivates the investigation of iron chelation strategies in cancer treatment. In a prochelation approach aimed at increasing intracellular specificity, disulfide reduction/activation switches are incorporated on iron-binding scaffolds resulting in intracellularly activated scavengers. Herein, this strategy is applied to several tridentate donor sets including thiosemicarbazones, aroylhydrazones and semicarbazones. The novel prochelator systems are antiproliferative in breast adenocarcinoma cell lines (MCF-7 and metastatic MDA-MB-231) and do not result in the intracellular generation of oxidative stress. Consistent with iron deprivation, the tested prochelators lead to cell-cycle arrest at the G1/S interface and induction of apoptosis. Notably, although hemoglobin-synthesizing blood cells have the highest iron need in the human body, no significant impact on hemoglobin production was observed in the MEL (murine erythroleukemia) model of differentiating erythroid cells. This study provides new information on the intracellular effects of disulfide-based prochelators and indicates aroylhydrazone (AH1-S)2 as a promising prototype of a new class of antiproliferative prochelator systems.

Propentdyopent: the scaffold of a heme metabolite as an electron reservoir in transition metal complexes.

The dipyrrin-1,9-dione scaffold of heme metabolite propendyopent coordinates late transition metals (Co, Ni, Cu, and Zn) forming homoleptic, pseudo-tetrahedral complexes. Electrochemical and spectroscopic studies reveal that the monoanionic, bidentate ligands behave as electron reservoirs as the complexes reversibly host one or two ligand-based radicals.

Sirtuin inhibitor sirtinol is an intracellular iron chelator.

Sirtinol is a known inhibitor of sirtuin proteins, a family of deacetylases involved in the pathophysiology of aging. Spectroscopic and structural data reveal that this compound is also an iron chelator forming high-spin ferric species in vitro and in cultured leukemia cells. Interactions with the highly regulated iron pool therefore contribute to its overall intracellular agenda.