title: Unprecedented oxidation of a biologically active aroylhydrazone chelator catalysed by iron(III): serendipitous identification of diacylhydrazine ligands with high iron chelation efficacy.
abstract: Ligands of the 2-pyridylcarbaldehyde isonicotinoylhydrazone class show high iron (Fe) sequestering efficacy and have potential as agents for the treatment of Fe overload disease. We have investigated the mechanisms responsible for their high activity. X-ray crystallography studies show that the tridentate chelate 2-pyridylcarbaldehyde isonicotinoylhydrazone undergoes an unexpected oxidation to isonicotinoyl(picolinoyl)hydrazine when complexed with FeIII. In contrast, in the absence of FeIII, the parent hydrazone is not oxidized in aerobic aqueous solution. To examine whether the diacylhydrazine could be responsible for the biological effects of 2-pyridylcarbaldehyde isonicotinoylhydrazone, their Fe chelation efficacy was compared. In contrast to its parent hydrazone, the diacylhydrazine showed little Fe chelation activity. Potentiometric titrations suggested that this might be because the diacylhydrazine was charged at physiological pH, hindering its access across membranes to intracellular Fe pools. In contrast, the Fe complex of this diacylhydrazine was charge neutral, which may allow facile movement through membranes. These data allow a model of Fe chelation for this compound to be proposed: the parent aroylhydrazone diffuses through cell membranes to bind Fe and is subsequently oxidized to the diacylhydrazine complex which then diffuses from the cell. Other diacylhydrazine analogues that were charge neutral at physiological pH demonstrated high Fe chelation efficacy. Thus, for this class of ligands, the charge of the chelator appears to be an important factor for determining their ability to access intracellular Fe. The results of this study are significant for understanding the biological activity of 2-pyridylcarbaldehyde isonicotinoylhydrazone and for the design of novel diacylhydrazine chelators for clinical use.
authors.affiliation: Department of Chemistry, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: P V
authors.initials: PV
authors.lastname: Bernhardt
authors.forename: P
authors.initials: P
authors.lastname: Chin
authors.forename: D R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D018360:Crystallography, X-Ray; D005290:Ferric Compounds / Q000737:chemistry*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019190:Iron Overload / Q000188:drug therapy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C404192:2-pyridylcarboxaldehyde isonicotinoylhydrazone; D005290:Ferric Compounds; D006834:Hydrazines; D006835:Hydrazones; D007502:Iron Chelating Agents; D011725:Pyridines