Novel diaroylhydrazine ligands as iron chelators: coordination chemistry and biological activity

The search for orally effective drugs for the treatment of iron overload disorders is an important goal in improving the health of patients suffering diseases such as β-thalassemia major. Herein, we report the syntheses and characterization of some new members of a series of N-aroyl-N′-picolinoyl hydrazine chelators (the H₂IPH analogs). Both 1:1 and 1:2 Fe^III:L complexes were isolated and the crystal structures of Fe(HPPH)Cl₂, Fe(4BBPH)Cl₂, Fe(HAPH)(APH) and Fe(H3BBPH)(3BBPH) were determined (H₂PPH=N,N′-bis-picolinoyl hydrazine; H₂APH=N-4-aminobenzoyl-N′-picolinoyl hydrazine, H₂3BBPH=N-3-bromobenzoyl-N′-picolinoylhydrazine and H₂4BBPH=N-(4-bromobenzoyl)-N′-(picolinoyl)hydrazine). In each case, a tridentate N,N,O coordination mode of each chelator with Fe was observed. The Fe^III complexes of these ligands have been synthesized and their structural, spectroscopic and electrochemical characterization are reported. Five of these new chelators, namely H₂BPH (N-(benzoyl)-N′-(picolinoyl)hydrazine), H₂TPH (N-(2-thienyl)-N′-(picolinoyl)-hydrazine), H₂PPH, H₂3BBPH and H₂4BBPH, showed high efficacy at mobilizing ⁵⁹Fe from cells and inhibiting ⁵⁹Fe uptake from the serum Fe transport protein, transferrin (Tf). Indeed, their activity was much greater than that found for the chelator in current clinical use, desferrioxamine (DFO), and similar to that observed for the orally active chelator, pyridoxal isonicotinoyl hydrazone (H₂PIH). The ability of the chelators to inhibit ⁵⁹Fe uptake could not be accounted for by direct chelation of ⁵⁹Fe from ⁵⁹Fe–Tf. The most effective chelators also showed low antiproliferative activity which was similar to or less than that observed with DFO, which is important in terms of their potential use as agents to treat Fe-overload disease.