FERRIC ION SEQUESTERING AGENTS: IRON REMOVAL IN MAN

本研究的目标包括：开发新的铁- 离子特异性螯合剂;这些药剂在 它们在体外从人转铁蛋白中去除铁的能力， 体内试验动物;机制表征 铁从转铁蛋白释放到更强的螯合剂; 合成配体在成像等应用中的评价 磁共振成像增强剂或Ga（III） 放射性药物 靶向的配体包括大环 儿茶酚配体应该具有预先形成的空腔， 对Fe（III）产生更大的稳定性和特异性。 模板 方法，其中3个儿茶酚基团首先在 金属离子，已被证明是一个实用的途径，以高- 产量，大规模合成这些材料。 几个新 类似于儿茶酚的羟基吡啶酮配体是 这些配体在低pH下是更好的络合剂 比儿茶酚更重要 配体的新方法， 催化从转铁蛋白中去除Fe（III），或者将被 口服有效。 越来越多地使用 金属络合物分光光度滴定数据 特征化使我们开发了改进程序， 利用所有这些数据。 线性代数方法对此 问题可以大大简化数值分析，同时也 使问题得到更好的解决。 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。 这是一个根本性 由于铁的快速消耗， 通过该项目产生的几种配体的去除。

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.