LV^VO-Ethyl Maltol-Based Metallodrugs (L^2– = 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′-(2-hydroxybenzylidene)furan-2-carbohydrazide; H2L2: (E)-N′-(4-(diethylamino)-2-hydroxybenzylidene)thiophene-2-carbohydrazide; H2L3: (E)-2-(4-(diethylamino)-2-hydroxybenzylideneamino)-4-methylphenol; 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 μM 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.