Iron is the most abundant transition metal found in living systems and plays a crucial role in multiple proteins involved in energy production (e.g. cytochrome <i>c</i>), oxygen transport, and DNA biosynthesis (ribonucleotide reductase).  To accommodate their higher replication rates, cancer cells require higher amounts of iron compared to their non-neoplastic counterparts. This higher demand for iron renders cancer cells susceptible to iron deprivation, and their exposure to iron chelators leads to growth arrest and cell death. Iron chelation strategies employing a wide variety of iron-binding scaffolds are currently under investigation for use in cancer treatment. Although these chelation approaches are effective against several cancer cell types, their use is limited due to toxicity ascribed to indiscriminant metal sequestration and induction of oxidative stress.  To overcome these issues, we have utilized a disulfide masking strategy on the well-studied thiosemicarbazone scaffold. Whereas disulfide-masked prochelators do not bind iron, reduction of the disulfide bond upon cellular uptake produces active chelators that readily bind intracellular iron. Unlike current iron chelators, these systems are not active extracellularly and target the intracellular labile iron pool.  We have designed and synthesized a series of prochelators and studied their antiproliferative activity and redox chemistry in cell culture. We found that these chelators present higher toxicities to cancer cell lines when compared to normal MRC-5 fibroblasts, with better selectivity than the clinically approved iron chelator DFO. The cytotoxicity of these disulfide masked prochelators is dependent on the intracellular redox environment, with enhanced toxicity in more reducing conditions. The iron complexes resulting from exposure of cultured cells to the chelation systems were detected intracellularly by electron paramagnetic resonance in intact frozen cells. The compounds in our first series do not engage in intracellular redox chemistry and do not cause oxidative stress.  In addition, we describe the development of synthetic methodologies for the preparation of mixed disulfides allowing conjugation of prochelators with tumor-targeting units. The resulting constructs are expected to present higher cancer selectivity and hence improved therapeutic indexes. This study is aimed at the molecular design and biological evaluation of new chelation strategies targeting iron in malignant cells.

Disulfide-masked thiosemicarbazone prochelators targeting the iron metabolism of cancer

251st National Meeting (2016)

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