IRON CHELATORS PREDICATED ON DESFERRITHIOCIN

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DESCRIPTION (adapted from the application) Iron overload secondary to transfusion therapy is life threatening in a variety of hematological disorders (e.g., Cooley's anemia, sickle cell anemia, and myelodysplasia). Management of the problem has relied heavily on treatment with desferrioxamine, a microbial iron chelator (siderophore) isolated from Streptomyces pilosus. However, because of side effects and the required continuous infusions, patient compliance has been problematic. Thus a great deal of effort has gone into the search for alternative therapeutics. Desferrithiocin (DFT), a siderophore isolated from S. antibioticus, was shown to be a very efficient, orally active iron chelator, but it also elicited nephrotoxicity. Nevertheless, its iron clearing efficiency and oral activity made desferrithiocin a very attractive target for structure-activity studies focused on ameliorating the ligand's toxic properties. As detailed in our Progress Report, during the present project period we have developed the tridentate ligands 4'-hydroxy-(S)-desazadesmethylDFT (25) and 4'-hydroxy-(S)-desazaDFT (28) as candidate orally active iron-chelating agents and a pentacoordinate unsymmetrical dihydroxamate DFT (31), which provided compelling reasons for the synthesis and consideration of DFT-based hexacoordinate ligands as candidate parenteral iron chelators. In our studies of these compounds, we have gained fundamental insights into the structure-activity relationships of the DFT framework, including its metabolism and pharmacokinetics that now provide the foundation for the design and synthesis of both tri-and hexadentate ligands with substantially enhanced efficiency. The overall goals of this renewal application continue to be the design, synthesis, and preclinical evaluation of the efficacy and safety of desferrithiocin-based iron-chelating agents. Thus, we propose to (1) design and synthesize tridentate orally active desferrithiocin-based chelators with enhanced efficiency through modifications which inhibit metabolic oxidative inactivation; (2) design and synthesize hexadentate chelators assembled from tridentate desferrithiocin fragments for evaluation as both orally and parenterally active agents; and (3) evaluate the efficacy and safety of these tri- and hexadentate desferrithiocin based compounds in mice, rats, gerbils, and primates as a function of their iron-loading status in preparation for human trials. When completed, these studies will significantly advance the development of improved therapeutic strategies for the management of iron overload, providing highly efficient chelators which would require substantially smaller, less frequent doses.