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.
