FERRIC ION SEQUESTERING AGENTS: IRON REMOVAL IN MAN

本研究的目标包括：新型铁粉的开发。 离子专用隔离剂.这些试剂在 它们在体外从人转铁蛋白中去除铁的能力和 来自体内的实验动物；机制的表征 铁从转铁蛋白释放到更强的螯合剂；以及 人工合成配体在影像领域的应用评价 磁共振成像增强剂或As，Ga(III) 放射性药物。目标配体包括大环 儿茶酚配体应具有预先形成的空穴以 对Fe(III)产生更大的稳定性和专属性。一个模板 方法，其中3个邻苯二酚基团首先在周围预先形成 金属离子，已被证明是一条可行的途径，以达到高- 产率，大规模合成这些材料。几个新的 类似于儿茶酚的羟基吡啶酸酯配体是 建议；这些配体在低pH值时是较好的络合剂 比儿茶团更重要。对配体的新方法将 催化从转铁蛋白中脱除Fe(III) 建议口服有效。越来越多的人使用 金属络合物中的分光光度滴定数据 特征描述使我们开发了精细化程序 利用所有这些数据。这一点的线性代数方法 问题可以极大地简化数值分析，同时 使问题变得更有条件。最后，一系列 表征铁的作用机制的实验方法 建议从转铁蛋白中释放。这是一个基本的 由于铁的速度很快，所以可以解决的问题 由这个项目产生的几个配体的去除。

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.