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

• Published in: Journal of biological inorganic chemistry Vol. 10; no. 7; pp. 761 - 777
• Main Authors: Bernhardt, Paul V, Chin, Piao, Sharpe, Philip C, Wang, Jing-Yan C, Richardson, Des R
• Format: Journal Article
• Language: English
• Published: Germany 01.11.2005
• Subjects: Carrier Proteins - chemistry; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Phenomena; Chemistry, Physical; Crystallography, X-Ray; Deferoxamine - chemistry; Drug Screening Assays, Antitumor; Electrochemistry; Humans; Hydrazines - chemistry; Iron - chemistry; Iron - metabolism; Iron Chelating Agents - chemistry; Iron Chelating Agents - pharmacology; Iron Radioisotopes - chemistry; Ligands; Lipids - chemistry; Models, Molecular; Potentiometry; Solutions; Structure-Activity Relationship; Transferrin - chemistry
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/s00775-005-0018-0

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 beta-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.