Fast biological iron chelators: kinetics of iron removal from human diferric transferrin by multidentate hydroxypyridonates

Abstract

For decades, desferrioxamine B (Desferal) has been the therapeutic iron chelator of choice for iron-overload treatment, despite numerous problems associated with its use. Consequently, there is a continuous search for new iron chelating agents with improved properties, particularly oral activity. We have studied new potential therapeutic iron sequestering agents: multidentate ligands containing the hydroxypyridonate (HOPO) moiety. The ligands TRENCAM-3,2-HOPO, TRPN-3,2-HOPO, TREN-Me-3,2-HOPO, TREN-1,2,3-HOPO, 5LIO-3,2-HOPO, and BU-O-3,4-HOPO have been examined for their ability to remove iron from human diferric transferrin. The iron removal ability of the HOPO ligands is compared with that of the hydroxamate desferrioxamine B, the catecholates TRENCAM and enterobactin, as well as the bidentate hydroxypyridonate deferiprone, a proposed therapeutic substitute for Desferal. All the tested HOPO ligands efficiently remove iron from diferric transferrin at millimolar concentrations, with a hyperbolic dependence on ligand concentration. At high ligand concentrations, the fastest rates are found with the tetra- and bidentate hydroxypyridonates 5LIO-3,2-HOPO and deferiprone, and the slowest rates with the catecholate ligands. At low concentrations, closer to therapeutic dosage, hexadentate ligands which possess high pM values have the fastest rates of iron removal. TRENCAM-3,2-HOPO and TREN-Me-3,2-HOPO are the most efficient at lower doses and are regarded as having high potential as therapeutic agents. The kinetics of removal of Ga(III) from transferrin [in place of the redox active Fe(III)] were performed with TRENCAM and TREN-Me-3,2-HOPO to determine that there is no catalytic reduction step involved in iron removal.