Coordination chemistry approaches to target cellular metal dysregulation

PROJECT SUMMARY Several transition metals are essential nutrients in human physiology: their acquisition and distribution are highly regulated, and alterations of metal homeostasis are associated with multiple pathological conditions including neurodegeneration and cancer. Metal-binding pharmaceuticals are employed clinically to treat metal overload; however, these chelators target systemic metals rather than intracellular metal dysregulation. Our research program aims at the design of chelation systems to increase the current understanding of metals in disease conditions and to modulate metal dysregulation for therapeutic applications in the long term. Our current experimental focus is on the role of iron in cancer progression. Because malignant cells require higher iron levels to sustain fast proliferation rates, we are engineering antiproliferative chelators that are activated upon cellular uptake to interfere with the availability of the labile iron pool. We employ disulfide bonds and arylsulfonate moieties as activation switches in prochelators that are activated following reaction with abundant thiols intracellularly. Exploiting the physiological differences between malignant and normal cells, we design bioconjugation approaches that increase the selectivity of prochelators for cancer cells. Further enhancing selectivity, we will also pursue the activation of prochelators by specific proteins that are overexpressed (or uniquely expressed) in cancer cells. In addition, we will deploy pro-oxidant strategies that enlist the redox chemistry of chelator-bound iron and copper complexes to generate reactive oxygen species in targeted cells. A new class of prochelators based on tetrazolium cations will be employed to pilot an initiative to image iron chelation via photoacoustic methods. Our experimental approach blends principles of coordination chemistry and chemical biology to produce a new generation of advanced chelation strategies. Detailed mechanistic studies will delineate the cellular uptake of our prochelators as well as their impact on cell cycle, cell death, and iron signaling. Because iron is a fundamental player in malignant behavior, this research offers opportunities to impact a broad spectrum of cancer phenotypes. These molecular design strategies are poised to enhance the scope of chelation in cancer research and potentially in other pathological conditions associated with metal dysregulation.