LV^VO-Ethyl Maltol-Based Metallodrugs (L^2– = Tridentate ONO Ligands): Hydrophobicity, Hydrolytic Stability, and Cytotoxicity via ROS-Mediated Apoptosis

Abstract

Four new oxidovanadium [V V OL 1–4 (ema)] complexes ( 1 – 4 ) have been synthesized using tridentate binegative ONO donor ligands H 2 L 1–4 [H 2 L 1: ( E )- N′ -(2-hydroxybenzylidene)furan-2-carbohydrazide; H 2 L 2: ( E )- N′ -(4-(diethylamino)-2-hydroxybenzylidene)thiophene-2-carbohydrazide; H 2 L 3: ( E )-2-(4-(diethylamino)-2-hydroxybenzylideneamino)-4-methylphenol; H 2 L 4: ( 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 (V V OL 1 -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 H 2 L 1–4 and 1 – 4 were tested against A549, HT-29, and NIH-3T3 cell lines. Among complexes, 2 with an IC 50 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.

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