THERAPEUTIC MULTIDENTATE IRON SEQUESTERING AGENTS

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DESCRIPTION (adapted from the application) Current strategies to prevent iron toxicity associated with transfusion induced hemosiderosis have a number of limitations. Desferrioxamine (Desferal) a tri-hydroxamate, is the most commonly used iron chelator. Desferal, is expensive, has a short half-life in vivo, does not efficiently remove iron from transferrin, must be given on a regular, frequent basis by a subcutaneous or intravenous route and its use can result in significant, irreversible toxicity. The bidentate dimethyl-3-hydroxypyridine-4-one, known as L1, DMHP, CP20 or Deferiprone, can catalyze iron removal from transferrin and has been shown to be effective when given orally. However, toxicity results with this agent, due in part to its thermodynamic instability and high concentration required to obtain a therapeutic effect. This application describes a plan to develop and evaluate a series of new iron chelating agents that are effective when administered orally and have no toxicity. Our hypothesis is that multidentate, rather than bidentate, hydroxypyridonate ligands will be effective as oral iron chelating agents and will not be toxic. Our specific aims will be to synthesize a variety of multidentate hydroxypyridonate ligands that are structurally designed so that they can decorporate iron from transferrin at low concentrations, have a long half-life in vivo, are therapeutically effective at removing excess iron when administered orally and are not toxic. Using a number of synthetic chemical steps, a series of novel iron chelating compounds with unique chemical structures, which have the potential to meet the above criteria, will be synthesized. The thermodynamics stability and kinetics of removal of iron from human transferrin will be determined for each compound. Two iron overloaded animal models will be used to evaluate toxicity, biological routes of iron excretion, and ability to remove iron from tissue stores. Our ultimate goal is to develop a safe, oral, clinically effective iron-chelating agent that will prevent the toxicity of iron accumulation in patients who require chronic red cell transfusions.