Unprecedented oxidation of a biologically active aroylhydrazone chelator catalysed by iron(III): serendipitous identification of diacylhydrazine ligands with high iron chelation efficacy

Ligands of the 2-pyridylcarbaldehyde isonicotinoylhydrazone class show high iron (Fe) sequestering efficacy and have potential as agents for the treat ment of Fe overload disease. We have investigated the mechanisms responsibl e for their high activity. X-ray crystallography studies show that the trid entate chelate 2-pyridylcarbaldehyde isonicotinoylhydrazone undergoes an un expected oxidation to isonicotinoyl(picolinoyl)hydrazine when complexed wit h Fe-III. In contrast, in the absence of Fel the parent hydrazone is not ox idized in aerobic aqueous solution. To examine whether the diacylhydrazine could be responsible for the biological effects of 2-pyridylcarbaldehyde is onicotinoylhydrazone, their Fe chelation efficacy was compared. In contrast to its parent hydrazone, the diacylhydrazine showed little Fe chelation ac tivity. Potentiometric titrations suggested that this might be because the diacylhydrazine was charged at physiological pH, hindering its access acros s 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 b e proposed: the parent aroylhydrazone diffuses through cell membranes to bi nd Fe and is subsequently oxidized to the diacylhydrazine complex which the n 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 impo rtant factor for determining their ability to access intracellular Fe. The results of this study are significant for understanding the biological acti vity of 2-pyridylcarbaldehyde isonicotinoylhydrazone and for the design of novel diacylhydrazine chelators for clinical use.