Iron, although crucial for life, is toxic if present in excessive amounts in the human body. Patients suffering from diseases, including hemochromatosis and ß-thalassemia major, accumulate, either directly or through repeated blood transfusions, high levels of iron in their vital organs, which rapidly leads to death through cardiac or liver failure if not treated. Currently, Desferal™ (desferrioxamine mesylate, DFO), a hexadentate hydroxamic acid, is still the only clinically approved iron chelator. This drug is very expensive and orally ineffective so patients must endure long periods (12-24 h/day, 5-6 days/week) of subcutaneous infusion of DFO to excrete these excessive levels of iron. These inherent limitations of DFO have prompted research in the search for alternatives.
We have developed a new aroylhydrazone class of iron chelators based on the parent ligands 2-pyridinecarbaldehyde isonicotinoyl hydrazone (HPCIH) and 2- pyrrolecarbaldehyde isonicotinoyl hydrazone (H2PRCIH). These are tridentate ligands capable of coordinating through the pyridine-N (or pyrrole-N), imine-N and carbonyl-0, forming bis-ligand iron complexes (FeL2) with N4O2 octahedral coordination sphere. Studies on ligands from the HPCIH series have revealed much greater iron-chelating efficacy than DFO in vitro and are promising as orally effective iron chelators. However, performance of the H2PRCIH series was unsatisfactory. Besides witnessing a complete de-activation of the ligands by substituting the pyridine ring with a pyrrole ring, it was also interesting to note that subtle changes to the non-coordinating pendant aromatic ring of the ligand resulted in pronounced changes in its iron chelation efficacy. We have also observed an unexpected ligand oxidation in Fll(PCIH)2 under aqueous aerobic conditions to give the ligand N-(isonicotinoyl)-N'-(picolinoyl) hydrazine (H2IPH) complexed to Felll, namely Felll(HIPH)(IPH). This has spawned a series of N,N'-diaroylhydrazine chelators, the H2IPH series. Our studies have shown that most of the H2IPH analogues exhibit similar iron-chelating efficacy to their hydrazone analogues, with just a couple of exceptions.
13, 6 and 8 analogues of the HPCIH, H2PRCIH and H2IPH series, respectively, have been synthesised and screened for iron chelation efficacy in an in vitro environment. Out of the 27 ligands, 5 of the HPCIH and 5 of the H2IPH analogues have displayed substantially greater activity than DFO. To better understand the biological activities of these ligands, we have studied the chemical and physical properties of these ligands and their iron complexes. Chiefly, we are concerned with the metal selectivity and affinity of the ligands, their biological barrier permeability in terms of protonation states and lipophilicity, as well as the redox chemistry of the metal complexes. The protonation constants of the ligands as well as the formation constants of their iron complexes were determined potentiometrically, and lipophilicity / hydrophilicity of the ligands and their iron complexes were determined by direct partitioning between 1-octanol and water. We have determined that the H2PRCIH and H2IPH analogues are Felll chelators, whereas the HPCIH analogues prefer Felll. Hence, HPCIH and HPCAH (2-pyridinecarbaldehyde-4- aminobenzoyl hydrazone) were used as model ligands to study the coordination chemistry of the HPCIH series with divalent metals of the first transition series, since several of these metals are physiologically important.
During the course of our investigation, we have discovered several interesting aspects of the coordination chemistry of these iron chelators. We have also investigated the oxidation of HPCIH to H2IPH catalysed by Felll, and have proposed a plausible mechanism for its occurrence.