FERRIC ION SEQUESTERING AGENTS--IRON REMOVAL

这项提案寻求继续支持开发新的 人铁超载的螯合治疗方法探讨 β-地中海贫血(库利氏贫血)的后果。该项目将 继续专注于三个目标：1)开发新的配体 费用+。2)新配体的热力学评价。3)生物性 新配体的评价。对于目标1，3-羟基-L的失败，2- 二甲基-4(1H)-吡啶酮(L1)在临床试验中再次强调 需要一种新的螯合剂来应对人类铁超载。这项研究 在我们的实验室里，L1的早期承诺继续指向 羟基吡啶(HOPO)配体是很有前途的。然而，有限的 简单双齿配体如L1-Make的热力学稳定性 与类似的六齿配体相比，这类配体的候选者较差。 我们现在有了合成程序来引入3，4-HOPO或3，2-HOPO 配体基团为具有最佳几何构型的六齿配体 Fe3+的八面体配位。但其他国家的情况却并非如此 到目前为止报道的是六齿配体。几条新的合成路线 3，2-和3，4-HOPO配体已被发现，并正在探索中。我们有 还发现，将一个儿茶酚基团加入到一个 多齿配体，如去铁胺B(三羟基甲酸酯配体 在目前的临床使用中)增加了从 人类铁转运蛋白转铁蛋白增加了两个数量级。它 建议通过将邻苯二酚基团结合来利用这一特性 转变为混合功能配体。新型配体的热力学稳定性 与Fe3+和竞争的生理金属离子将被检测。一个 最初的生物筛查将是铁的去除速度 转铁蛋白。哺乳动物与铁交换的动力学和机制 将研究铁储存和运输蛋白。初步毒性 研究将与P.Durbin博士合作进行。 将对最有希望的患者进行除铁筛查 与R.Bergeron博士合作开发的化合物。

This proposal seeks continuation of support for a project to develop new approaches to the chelation therapy of human iron overload that is a consequence of beta-thalassemia (Cooley's anemia). The project will continue to focus on three goals: 1) The development of new ligands for Fee+. 2) The thermodynamic evaluation of new ligands. 3) The biological evaluation of new ligands. For goal #1, the failure of 3-hydroxy-l, 2- dimethyl-4(1H) -pyridinone (L1) in clinical trials has again emphasized the need for a new chelating agent for human iron overload. The research in our laboratories and the early promise of L1 continue to point toward hydroxypyridonate (HOPO) ligands as promising. However the limited thermodynamic stability of a simple bidentate ligand such as L1 makes such ligands poor candidates relative to analogous hexadentate ligands. We now have synthetic procedures to introduce either 3,4-HOPO or 3,2-HOPO ligand groups into hexadentate ligands with a geometry optimal for octahedral coordination to Fe3+. This has not been true of other hexadentate ligands reported to date. Several new - synthetic routes to 3,2- and 3,4-HOPO ligands have been found and are being explored. We have also found that the incorporation of one catechol group into a multidentate ligand such as desferrioxamine B (the trihydroxamate ligand in current clinical use) increases the rate of iron removal from the human iron transport protein transferrin by two orders of magnitude. It is proposed that this feature be exploited by combining catechol groups into mixed function ligands. The thermodynamic stability of new ligands with Fe3+ and competing physiological metal ions will be examined. An initial biological screen will be the rate of iron removal from transferrin. The kinetics and mechanisms of iron exchange with mammalian iron storage and transport proteins will be studied. Preliminary toxicity studies will be carried out in collaboration with Dr. P. Durbin. Screening for iron removal will be carried out for the most promising compounds in collaboration with Dr. R. Bergeron.