FERRIC ION SEQUESTERING AGENTS--IRON REMOVAL

这项建议寻求继续支持一个项目， 人类铁超载的螯合治疗方法， β地中海贫血（Cooley贫血）。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 新配体的评价。对于目标#1，3-羟基-1，2-二氢吡喃的失败是由于目标#1的3-羟基-1，2-二氢吡喃的失败。 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治疗人体铁超载。研究 在我们的实验室里，L1的早期承诺继续指向 羟基吡啶酮（HOPO）配体。然而，有限的 简单的双齿配体如L1的热力学稳定性使得 这样的配体相对于类似的六齿配体而言是较差的候选物。 我们现在有合成方法来引入3，4-HOPO或3，2-HOPO 配体基团转化为六齿配体，其具有最佳的几何构型， 八面体配位到Fe 3+。其他国家的情况并非如此。 六齿配体的报道。几种新的合成路线， 3，2-和3，4-HOPO配体已经被发现并正在探索中。我们有 还发现，将一个儿茶酚基团并入一个 多齿配体如去铁胺B（三异羟肟酸配体 在目前的临床使用中）增加了从 人铁转运蛋白转铁蛋白两个数量级。它 提出，这一特点是利用结合邻苯二酚组 混合功能配体。新配体的热力学稳定性 与Fe 3+和竞争性生理金属离子。 一个 最初的生物筛选将是铁的去除率， 转铁蛋白哺乳动物铁交换的动力学及机制 铁储存和转运蛋白将被研究。初步毒性 研究将与P. Durbin博士合作进行。 筛选除铁将进行最有前途的 与R博士合作。贝杰隆

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.