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FERRIC ION SEQUESTERING AGENTS--IRON REMOVAL

三价铁离子螯合剂--除铁

基本信息

批准号：
6070716
负责人：
KENNETH N RAYMOND
金额：
$ 6.26万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-11-30 至 1999-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6070716
关键词：
catechols chelating agents chelation therapy chemical group chemical stability deferoxamine drug design /synthesis /production iron ligands pyridinones thalassemia thermodynamics transferrin transport proteins

项目摘要

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.

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。