IRON CHELATORS PREDICATED ON DESFERRITHIOCIN

描述（改编自应用程序） 继发于输血治疗的铁超负荷在多种情况下危及生命。 血液疾病（例如，库利氏贫血，镰状细胞贫血， 脊髓发育不良）。这个问题的管理在很大程度上依赖于治疗， 去铁胺，一种微生物铁螯合剂（铁载体），分离自 链霉菌。然而，由于副作用和所需的 连续输注，患者依从性一直是个问题。一个伟大的 大量的努力已经投入到寻找替代疗法中。 去铁硫菌素（DFT）是从S.显示的是， 是一种非常有效的口服活性铁螯合剂，但它也引起了 肾毒性然而，其铁清除效率和口服活性 使去铁硫菌素成为结构-活性研究的一个非常有吸引力的靶点 专注于改善配体的毒性。如我们的 进度报告，在本项目期间，我们制定了 三齿配体4 '-羟基-（S）-脱氮基甲基DFT（25）和 作为候选口服活性铁螯合剂的4 '-羟基-（S）-脱氮DFT（28） 和五配位不对称二异羟肟酸酯DFT（31），其提供 综合和审议基于DFT的 六配位配体作为候选肠胃外铁螯合剂。在我们的研究中 这些化合物，我们已经获得了基本的见解， DFT框架的结构-活性关系，包括其代谢 和药代动力学，现在为设计和 合成三齿和六齿配体， 效率此更新应用程序的总体目标仍然是 的设计、合成和临床前评价 基于去铁硫菌素的铁螯合剂。 因此，我们提出：（1）设计合成三齿口服活性物质 通过修饰而提高效率的基于去铁硫菌素的螯合剂 其抑制代谢氧化失活;（2）设计和合成 由三齿去铁硫菌素片段组装的六齿螯合剂， 作为口服和胃肠外活性剂的评价;和（3）评价 这些基于三齿和六齿去铁硫菌素的有效性和安全性 在小鼠、大鼠、沙鼠和灵长类动物中， 为人体试验做准备。完成后，这些 这些研究将大大促进改善治疗的发展， 铁超载的管理策略，提供高效的 螯合剂，其需要显著更小、更少频率的剂量。

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.