Interactions of the pyridine-2-carboxaldehyde isonicotinoyl hydrazone class of chelators with iron and DNA: implications for toxicity in the treatment of iron overload disease

Iron chelation therapy for the management of iron-overload disease is dominated by desferrioxamine (DFO). However, treatment using DFO is very arduous. Recently, novel Fe chelators of the pyridine-2-carboxaldehyde isonicotinoyl hydrazone (PCIH) class have shown high chelation efficacy and the potential to replace DFO. A critical consideration in the design of alternatives to DFO is that the chelator forms a redox-inert Fe complex. In the present study, the participation of Fe complexes in redox reactions has been investigated. Ascorbate oxidation in the presence of Fe(III) or benzoate hydroxylation in the presence of Fe(II) was not enhanced by the PCIH analogues. However, redox-induced DNA strand breaks were observed with these ligands under highly oxidizing conditions in the presence of Fe(II) and hydrogen peroxide. Experiments then examined the interactions of the PCIH analogues with DNA, and this was found to be weak. Considering this, we suggest that under extreme conditions seen in the DNA-strand break assay, weak DNA-binding may potentiate the redox activity of the PCIH analogues. However, importantly, in contrast to naked plasmid DNA, DNA damage by these chelators using intact human cells was not significant. Collectively, our results support the potential of the PCIH analogues for the treatment of Fe overload.