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.

Hydrazone chelators for the treatment of iron overload disorders: iron coordination chemistry and biological activity

“…The complexes Fe(PCNH) 2 , Fe(PC4AH) 2 and Fe(PC3AH) 2 each exhibited 4 of the 5 expected peaks from the pyridine carbaldehyde moiety while all other complexes gave only 3 resonances with a large downfield shift. In our previous study with the Fe(PKIH) 2 analogues, 36 we showed that the proton most affected by paramagnetism was that in the 6-position of the coordinated pyridyl ring although in that case the paramagnetism was only very mild by comparison. Extrapolating to this system, we believe that the NMR resonance for the proton attached to atom C1 in Fig.…”

“…This is similar behaviour to that reported in the electrochemistry of the related Fe(PKIH) 2 complexes. 36 Of note, is the significantly more negative potentials exhibited by Fe(PCAH) 2 . This is consistent with the strong electron-donating effect of the 4-aminophenyl substituent disfavouring both metal and ligand based reductions.…”

“…17, 36 Redox-active Fe complexes that are negatively charged such as [Fe(EDTA)] 2− are repelled by like-charged DNA and show no significant plasmid degradation.…”

A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

“…Furthermore, upon PKIH and DpT ligands forming Fe complexes, these ligands generate cytotoxic ROS (10,(26)(27)(28). The resulting oxidative damage potentiates the antiproliferative activity of PKIH and DpT chelators compared with 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone or DFO, which bind Fe but do not redox cycle (29).…”

“…The resulting oxidative damage potentiates the antiproliferative activity of PKIH and DpT chelators compared with 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone or DFO, which bind Fe but do not redox cycle (29). The higher activity of DpT series relative to the PKIH class can be ascribed, at least in part, to the electrochemical potentials of their Fe complexes (26,28). In fact, the Fe III/II redox potentials of the Fe(DpT) 2 complexes (ϩ153-225 mV) are much lower than the PKIH analogs (approximately ϩ500 mV) and lie in a range accessible to cellular oxidants and reductants (26,28).…”