Due to their rapid proliferation rates, cancer cells have a higher iron demand when compared to normal cells and are typically more susceptible to iron deprivation, which halts growth and  ultimately causes cell death. As such, iron chelation strategies are emerging in experimental approaches for cancer chemotherapy.  Thiosemicarbazones, a class of iron scavengers, have been shown to be effective against several cancer cell types in vivo and in vitro. Nevertheless, their applicability in experimental cancer treatment is limited, owing to toxicity and side effects that have been attributed to indiscriminant metal chelation and induction of oxidative stress.  To overcome such issues, we have developed a reduction/activation strategy that exploits the intracellular redox environment of cancerous cells, which is governed by the glutathione (GSH) redox buffer. Because GSH levels are higher in cancer tissue as compared to neighboring normal tissue, GSH can be employed for the preferential activation of pro-drugs by reduction in malignant tissue.  Our approach takes advantage of this property by masking thiosemicarbazone pro-chelators with a disulfide bond, which can then be intracellularly reduced by glutathione thereby activating the pro-chelator for metal sequestration.  Herein, we investigate the reduction of the disulfide bond of masked pro-chelator systems in vitro and intracellularly, as well as their ability to sequester iron intracellularly and to induce oxidative stress. We validate the disulfide reduction/activation strategy and demonstrate the intracellular formation of low-spin iron(III) complexes. In addition, we investigate in live cells the effect of our chelation systems on the active site of iron-dependent ribonucleotide reductase, a key enzyme in DNA biosynthesis and therefore an essential component of cell proliferation. This study shows that disulfide switches can be employed for effective redox-directed strategies for intracellular iron chelation.

Disulfide-masked thiosemicarbazone chelators for intracellular iron sequestration

248th National Meeting (2014)

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