SYNTHESIS, PHYSICOCHEMICAL PROPERTIES, AND BIOLOGICAL EVALUATION OF N-SUBSTITUTED 2-ALKYL-3-HYDROXY-4(1H)-PYRIDINONES - ORALLY-ACTIVE IRON CHELATORS WITH CLINICAL POTENTIAL

The synthesis of a range of novel bidentate ligands containing the che lating moiety 3-hydroxy-4(1H)-pyridinone is described. The pK(a) value s of the ligands and the stability constants of their iron(III) comple xes have been determined. The crystal structures of one of the ligands and one of the iron(III) complexes are presented. The distribution co efficients of the ligands are reported and are related to the ability of the ligands to remove iron from hepatocytes. The influence of 3-hyd roxy-4(1H)-pyridinones on oxidative damage to cells is described. In c ontrast to the iron chelator in current therapeutic use, desferrioxami ne-B, many of the bidentate ligands described in this study are orally active in iron-overloaded mice.