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Tridentate thiosemicarbazones, among several families of iron chelators, have shown promising results in anticancer drug discovery because they target the increased need for iron that characterizes malignant cells. Prochelation strategies, in which the chelator is released under specific conditions, have the potential to avoid off-target metal binding (for instance, in the bloodstream) and minimize unwanted side effects. We report a prochelation approach that employs arylsulfonate esters to mask the phenolate donor of salicylaldehyde-based chelators. The new prochelators liberate a tridentate thiosemicarbazone intracellularly upon reaction with abundant nucleophile glutathione (GSH). A 5-bromo-substituted salicylaldehyde thiosemicarbazone (STC4) was selected for the chelator unit because of its antiproliferative activity at low micromolar levels in a panel of six cancer cell lines. The arylsulfonate prochelators were assessed in vitro with respect to their stability, ability to abolish metal binding, and reactivity in the presence of GSH. Cell-based assays indicated that the arylsulfonate-masked prochelators present higher antiproliferative activities relative to the parent compound after 24 h. The activation and release of the chelator intracellularly were corroborated by assays of cytosolic iron binding and iron supplementation effects as well as cell cycle analysis. This study introduces the 1,3,4-thiadiazole sulfonate moiety to mask the phenolate donor of an iron chelator and impart good solubility and stability to prochelator constructs. The reactivity of these systems can be tuned to release the chelator at high glutathione levels, as encountered in several cancer phenotypes.

Tridentate aroyl hydrazones are effective metal chelators in biological settings, and their activity has been investigated extensively for medicinal applications in metal overload, cancer, and neur...

The central role of iron in tumor progression and metastasis motivates the development of iron-binding approaches in cancer chemotherapy. Disulfide-based prochelators are reductively activated upon cellular uptake to liberate thiol chelators responsible for iron sequestration. Herein, a trimethyl thiosemicarbazone moiety and the imidazole-2-thione heterocycle are incorporated in this prochelator design. Iron binding of the corresponding tridentate chelators leads to the stabilization of a low-spin ferric center in 2 : 1 ligand-to-metal complexes. Native mass spectrometry experiments show that the prochelators form stable disulfide conjugates with bovine serum albumin, thus affording novel bioconjugate prochelator systems. Antiproliferative activities at sub-micromolar levels are recorded in a panel of breast, ovarian and colorectal cancer cells, along with significantly lower activity in normal fibroblasts.