Structure-Activity Relationships of Novel Salicylaldehyde Isonicotinoyl Hydrazone (SIH) Analogs: Iron Chelation, Anti-Oxidant and Cytotoxic Properties

Abstract

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.

Disulfide-masked iron prochelators: Effects on cell death, proliferation, and hemoglobin production

“…The selected compounds allowed comparison of binding groups with (S,N,S) and (S,N,O) donor sets, as well as different functional groups (e.g., aroyl hydrazones vs semicarbazones within the (S,N,O) binding units). In addition, methyl hydrazone analogs were included because studies on SIH and related high-affinity hydrazone chelators indicated that these derivatives are more stable with respect to hydrolytic degradation [42].…”

Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents

“…The fluorimetric calcein-AM assay was performed by established methods, as described previously [ 38 , 39 ]. The Fe chelation efficiency of the metabolites in cells was expressed as a percentage of that of the parent chelator, Dp44mT or DpC (100%).…”

“…The Fe chelation efficiency of the metabolites in cells was expressed as a percentage of that of the parent chelator, Dp44mT or DpC (100%). For studies assessing the ability of these agents to induce 59 Fe mobilization and inhibit 59 Fe uptake from 59 Fe-transferrin by cells, human transferrin (Sigma-Aldrich, Germany) was labeled with 59 Fe (PerkinElmer, MA, USA) to generate 59 Fe-transferrin at a final specific activity of 500 pCi/pmol Fe, as previously described [ 22 , 39 , 40 ]. The unbound 59 Fe was removed by exhaustive vacuum dialysis against a large excess of 0.15 M NaCl buffered to pH 7.4 with 1.4% NaHCO 3 by standard methods [ 22 , 40 ].…”

Design, Synthesis and Evaluation of Antiproliferative Activity of New Benzimidazolehydrazones

“…4-(2-Fluorophenoxy)quinolineacylhydrazones showed excellent antiproliferative activity and c-Met kinase inhibitory activity [13]. Salicylaldehyde isonicotinoylhydrazone analogs behaved as iron chelators especially in MCF-7 breast adenocarcinoma cells and this was correlated to their cytotoxic activity [14], while salicylaldehyde 1-arylmethyl-3-aryl-1 H -pyrazole-5-carbohydrazide hydrazone derivatives inhibited the growth of A549 lung cancer cells [15]. We have previously reported on 2-arylamino-6-trifluoromethyl-3-(hydrazinocarbonyl)pyridines [16] showing in vitro inhibitory activity against human tumour cell lines at low micromolar to nanomolar concentrations.…”