FERRIC ION SEQUESTERING AGENTS: IRON REMOVAL IN MAN

三价铁离子螯合剂：人体除铁

• 批准号: 3231397
• 负责人: KENNETH N RAYMOND
• 金额: $ 16.28万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-11-30 至 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3231397
• 关键词: catechols; chelating agents; chelation therapy; chemical reaction; contrast media; deferoxamine; drug administration rate /duration; drug design /synthesis /production; electrochemistry; heart disorder; iron storage disorder; liver disorder; nuclear magnetic resonance spectroscopy; orphan disease /drug; pancreas disorder; radiopharmacology; sickle cell anemia; thalassemia; thermodynamics; transferrin

The goals of this research include: the development of new ferric- ion-specific sequestering agents; the evaluation of those agents in their ability to remove iron from human transferrin in vitro and from test animals in vivo; the characterization of the mechanism of iron release from transferrin to stronger chelating agents; and the evaluation of synthesized ligands in applications as imaging agents in magnetic resonance imaging enhancement or as Ga(III) radiopharmaceuticals. The ligands targeted include macrocyclic catecholate ligands which should have preformed cavities to generate greater stability and specificity for Fe(III). A template approach, in which 3 catechol groups are first pre-formed around the metal ion, has been shown to be a practical route to the high- yield, large-scale synthesis of these materials. Several new hydroxypyridonate ligands analogous to the catechols are proposed; these ligands are better complexing agents at low pH than are the catechols. New approaches to ligands which will catalyze the removal of Fe(III) from transferrin or which will be orally effective are proposed. The increasing use of spectrophotometric titration data in metal-complex characterization has led us to develop refinement procedures utilizing all such data. Linear algebraic approaches to this problem can greatly simplify the numerical analysis while also making the problem much better conditioned. Finally, a series of experimental approaches to characterize the mechanism of iron release from transferrin is proposed. This is a fundamental problem which is accessible because of the rapid rate of iron removal by several of the ligands resulting from this project.

这项研究的目标包括：开发新的铁- 离子特异性螯合剂；对这些代理人的评价 他们在体外从人转铁蛋白中去除铁的能力 来自试验动物体内；机制的表征 铁从转铁蛋白释放到更强的螯合剂；和 合成配体在成像应用中的评估 磁共振成像增强剂或 Ga(III) 放射性药物。 靶向配体包括大环 儿茶酚酸酯配体应具有预先形成的空腔 对 Fe(III) 产生更高的稳定性和特异性。 一个模板 方法，其中首先围绕 金属离子已被证明是一种实用的途径 产量，大规模合成这些材料。 几款新品 与儿茶酚类似的羟基吡啶酮酸配体是 建议的;这些配体在低 pH 条件下是更好的络合剂 比儿茶酚更重要。 配体的新方法将 催化从转铁蛋白中去除 Fe(III) 或 建议口服有效。 越来越多的使用 金属络合物的分光光度滴定数据 表征使我们开发了细化程序 利用所有此类数据。 线性代数方法解决这个问题 问题可以大大简化数值分析，同时也 使问题得到更好的调节。 最后，一系列 表征铁机制的实验方法 建议从转铁蛋白中释放。 这是一个基本的 由于铁的快速消耗，这个问题是可以解决的 被该项目产生的几种配体去除。