title: Cytotoxic iron chelators: characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues.
abstract: Di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and a range of its analogues comprise a series of monobasic acids that are capable of binding iron (Fe) as tridentate ( N, N, O) ligands. Recently, we have shown that these chelators are highly cytotoxic, but show selective activity against cancer cells. Particularly interesting was the fact that cytotoxicity of theHPKIH analogues is maintained even after complexation with Fe. To understand the potent anti-tumor activity of these compounds, we have fully characterized their chemical properties. This included examination of the solution chemistry and X-ray crystal structures of both the ligands and Fe complexes from this class and the ability of these complexes to mediate redox reactions. Potentiometric titrations demonstrated that all chelators are present predominantly in their charge-neutral form at physiological pH (7.4), allowing access across biological membranes. Keto-enol tautomerism of the ligands was identified, with the tautomers exhibiting distinctly different protonation constants. Interestingly, the chelators form low-spin (diamagnetic) divalent Fe complexes in solution. The chelators form distorted octahedral complexes with Fe(II), with two tridentate ligands arranged in a meridional fashion. Electrochemistry of the Fe complexes in both aqueous and non-aqueous solutions revealed that the complexes are oxidized to their ferric form at relatively high potentials, but this oxidation is coupled to a rapid reaction with water to form a hydrated (carbinolamine) derivative, leading to irreversible electrochemistry. The Fe complexes of theHPKIH analogues caused marked DNA degradation in the presence of hydrogen peroxide. This observation confirms that Fe complexes from theHPKIH series mediate Fenton chemistry and do not repel DNA. Collectively, studies on the solution chemistry and structure of theseHPKIH analogues indicate that they can bind cellular Fe and enhance its redox activity, resulting in oxidative damage to vital biomolecules.
authors.affiliation: Department of Chemistry, University of Queensland, 4072 Brisbane, Australia. p.bernhardt@uq.edu.au
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Caldwell
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Chaston
authors.forename: Piao
authors.initials: P
authors.lastname: Chin
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D004563:Electrochemistry; D006835:Hydrazones / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D008024:Ligands; D010084:Oxidation-Reduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects
chemical_list: D006835:Hydrazones; D007502:Iron Chelating Agents; D008024:Ligands; C001097:di-2-pyridylketoxime; D015082:2,2'-Dipyridyl