IRON CHELATORS PREDICATED ON DESFERRITHIOCIN

说明(改编自应用程序) 输血治疗后继发的铁超载在各种情况下都危及生命 血液系统疾病(例如，库利氏贫血、镰状细胞性贫血和 骨髓发育不良症)。这个问题的管理在很大程度上依赖于 去铁胺，一种微生物铁络合剂(铁载体)，从 毛状链霉菌。然而，由于副作用和所需的 持续输液，患者的依从性一直存在问题。因此，一个伟大的 在寻找替代疗法方面已经付出了大量努力。 脱铁硫蛋白(DFT)是一种从抗生素链霉菌中分离出来的铁载体。 是一种非常有效的口服活性铁络合剂，但它也引发了 肾毒性。然而，它的清铁效率和口腔活动 使去铁硫蛋白成为结构活性研究的一个非常有吸引力的目标 专注于改善配体的毒性性质。正如我们的 进度报告，在本项目期间，我们制定了 三齿配体4‘-羟基-(S)-去氮杂甲基DFT(25)和 4‘-羟基-(S)-地氮杂DFT(28)作为候选口服活性铁络合剂 和五配位不对称二羟基甲酸酯DFT(31)，其提供 基于DFT合成和考虑的令人信服的理由 六配位配体作为候选的肠外铁络合剂。在我们的研究 在这些化合物中，我们已经获得了对 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 大幅度增强的三齿和六齿配体的合成 效率。此续订申请的总体目标仍然是 阿司匹林的有效性和安全性的设计、合成和临床前评估 去铁硫辛型铁络合剂。 因此，我们建议(1)设计和合成口服活性三齿 通过修饰提高效率的去铁硫辛基络合剂 抑制代谢氧化失活；(2)设计合成 由三齿脱铁硫蛋白片段组装的六齿螯合剂用于 评价为口服和非肠道活性药物；以及(3)评价 这些三齿和六齿去铁硫蛋白的疗效和安全性 小鼠、大鼠、沙土鼠和灵长类动物中的化合物 为人体试验做准备的铁负荷状况。完工后，这些 研究将显著推动改进治疗方法的发展 管理铁超载的策略，提供高效 螯合剂需要的剂量要小得多，频率也更低。

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.