ChemInform Abstract: Development of Iron Chelators for Cooley′s Anemia.

Abstract

Abstract The rationale employed in the design of new chelating ligands for strong binding of Fe(III) at physiological pH for the treatment of iron overload disease such as Cooley's anemia is explained and the preparation and evaluation of forty new iron(III) chelators are described. The new ligands investigated include the following classifications: five analogs of ethylenediaminetetraacetic acid (EDTA) with amino and carboxylate donor groups; ten ligands with phenolic (or potential phenolic) donor groups in addition to amino and carboxylate donors: five ligands containing phenolic groups substituted on pyridine rings in addition to amino and carboxylate donors; six aminophosphonic acid or ester groups with additional phenolate and amino donors; eight macrocyclic polyamines containing auxiliary carboxylate and/or phenolate donor groups; three trishydroxamic acids; two triscatechols; and one multi- dentate ligand with coordinating amide groups. These chelating agents were administered to male BDF 1 hybrid mice overloaded with iron by blood transfusion. Fecal and urinary elimination of iron were measured, as well as the retention of iron in the spleen and liver. The results are compared with the action of desferriferrioxamine B (DFB). Potencies relative to a Desferal® dose of 250 mg/kg tested simultaneously and assigned a potency of 1.0 are reported, and relative toxicities ( LD 50s and toxic signs) are also described. Nine of the ligands tested showed sufficient potency to warrant further development as iron chelating drugs, while six of them have potencies comparable to or greater than that of DFB.