Small Molecule Regulation of Iron Homeostasis: Design and Optimization of Novel Iron Chelators Based on a Thiosemicarbazone Scaffold.

Disrupted iron balance causes anemia and iron overload leading to hypoxia and systemic oxidative stress. Iron overload may arise from red blood cell disorders such as sickle cell disease, thalassemia major and primary hemochromatosis, or from treatment with multiple transfusions. These hematological disorders are characterized by constant red blood cell hemolysis and the release of iron. Hemolysis is a continuous source of reactive oxygen species whose accumulation changes the redox potential in the erythrocyte, the endothelium and other tissue causing damage to organ systems. Iron overload and its consequences can be treated with iron chelating therapy. We have carried out structural studies of small molecule ligands that were previously reported for their iron chelating ability. The chelators were analyzed using mass spectrometry, proton nuclear magnetic resonance and infrared spectroscopy. The iron chelators, 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone, 3-ethyl-1-{[2-phenyl-1-(pyridin-2-yl)ethylidene]amino}thiourea and 1-{[2-phenyl-1-(pyridin-2-yl)ethylidene]amino}-3-(prop-2-en-1-yl)thiourea in their unbound conformation were crystallized and their structures were determined. This work addresses the evolution of a thiosemicarbazone class of iron chelators by analyzing and comparing the structure and properties of a series of closely related molecules, relating these to their