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.