It is planned to synthesize 30-40 new organic ligands having affinity and selectivity for ferric ion, to test their toxicities and compatibilities in animal systems, and determine their effectiveness in the removal of iron from physiological systems. The new reagents will form iron complexes with thermodynamic stabilities orders of magnitude higher than those of the natural iron transport protein transferrin and the iron storage protein ferritin, and can be expected to remove iron form these proteins as well as from other natural receptors with which the iron may be combined in iron overload patients. The new drugs will be developed by the use of modern methods of ligand design and will emphasize macrocyclic and macrobicyclic ligand, which have not been thoroughly explored in past developmental work on drugs for iron overload disease. The group at Texas A&M will synthesize the new drugs, measure the thermodynamic stabilities and rates of formation of their iron(II) complexes in solution, and the rates of iron removal from iron proteins. The new ligands will be evaluated in vivo at Washington University. The effectiveness of new ligands to increase excretion of iron will be studied using radioactive tracer techniques in animals which have been pretreated with radiolabeled iron. The radiolabeled iron will be administered either in the form of a weal chelate or in liposomes in order to evaluate the effect of the chelates on iron in the vascular system or iron trapped in the liver. Toxicities of the new chelators will be determined, and those having sufficiently low toxicity will be tested for route of elimination of the organic ligands by C-14 tracer studies.
