Iron plays a central role in cancer growth by supporting enhanced proliferation and survival of malignant cells as well as by remodeling the tumor microenvironment to facilitate motility and metastatic behavior. Several iron chelators have shown promising results in clinical trials for cancer indications; however, no iron-sequestering compound is currently approved for cancer treatment. To increase the selectivity and efficacy of iron-binding approaches, we are exploring strategies to release iron chelators only after cellular uptake. Reductive activation strategies are particularly advantageous owing to the more reducing conditions found in malignant cells when compared to neighboring normal cells. The reduction of disulfide bonds and the reactivity of arylsulfonate groups in the presence of high glutathione concentrations is employed to liberate thiolate or phenolate donors of tridentate thiosemicarbazone and aroylhydrazone moieties. Furthermore, the conjugation of carbohydrate moieties to the prochelator structure can be employed to facilitate accumulation in malignant cells overexpressing the glucose receptors as observed in several cancer phenotypes. Overall, the molecular engineering of prochelators is expected to improve the ability of iron-sequestration approaches to target cancer growth while minimizing unwanted side effects.

Engineering intracellular iron sequestration to target cancer growth

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