Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate
iron chelator with marked
anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its
hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic
ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma,
iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast
adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these
chelators and their ability to afford protection against
hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The
ligands with a reduced
hydrazone bond, or the presence of bulky alkyl substituents near the
hydrazone bond, showed severely limited
biological activity. The introduction of a
bromine substituent increased
ligand-induced cytotoxicity to both
cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with
pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the
hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast
adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone
iron chelators with more potent and selective anti-neoplastic effects.