LVVO-Ethyl Maltol-Based Metallodrugs (L2-= Tridentate ONO Ligands): Hydrophobicity, Hydrolytic Stability, and Cytotoxicity via ROS-Mediated Apoptosis

Four new oxidovanadium [VVOL1-4(ema)] complexes (1-4) have been synthesized using tridentate binegative ONO donor ligands H2L1 -4 [H2L1: (E)-N '-( 2hydroxybenzylidene)furan-2-carbohydrazide; H2L2: (E)-N '-(4-(di-ethylamino)-2-hydroxybenzylidene)thiophene-2-carbohydrazide; H2L3: (E)-2-(4-(diethylamino)-2-hydroxybenzylideneamino)-4methylphenol; H2L4: (E)-2-(3-ethoxy-2-hydroxybenzylideneamino)-4-methylphenol] and ethyl maltol (Hema) as a bidentate uninegative coligand and characterized by CHNS analysis, IR, UV-vis, NMR, and HR-ESI-MS methods. The structures of 1, 3, and 4 are confirmed by single-crystal X-ray analysis. The hydrophobicity and hydrolytic stability of the complexes are tested using NMR and HR-ESI-MS and correlated with their observed biological activities. It is observed that 1 hydrolyzed into a penta-coordinated vanadium-hydroxyl species (VVOL1-OH) with the release of ethyl maltol, whereas 2-4 are found quite stable under the investigated time period. The biomolecular interaction of 1-4 with DNA and BSA was performed using absorbance, fluorescence, and circular dichroism techniques. The in vitro cytotoxicity activities of H2L1-4 and 1-4 were tested against A549, HT-29, and NIH-3T3 cell lines. Among complexes, 2 with an IC50 value of 4.4 +/- 0.1 mu M displayed maximum anticancer activity against the HT-29 cell line. Complexes induce cell cycle arrest at the G2/M phase and subsequently trigger dose-dependent cell apoptosis, which is obtained by the cell apoptosis analysis via flow cytometry and confocal microscopy assays. Being fluorescence active, 1-4 were observed to target the mitochondria and exhibit disruption of the mitochondrial membrane potential, which consequently causes overproduction of intracellular reactive oxygen species and induced cell apoptosis.