Insights into the transformation of VO2+ motif to VO3+, V2O34+ and VO2+ motifs and their interconversion along with a detailed mechanistic study of their anti-cancer activity in SiHa cervical cancer cells

Abstract

The basic criteria for the formation of complexes with VO3+, V2O34+ and VO2+ motifs from the VO2+ motif and their interconversion were explored utilizing two multidentate O,N-donor hydrazone ligands namely, E-2-Hydroxy-N′-(4-oxopentan-2-ylidine)benzohydrazide (H3L1) and E-2-Hydroxy-N′-(4-oxo-4-phenylbutan-2-ylidine)benzohydrazide (H3L2), derived from the condensation of 2-hydroxybenzoylhydrazide with acetylacetone and benzoylacetone respectively. Under aerobic condition, the possibility of forming complexes with different motifs in different solvents with varying pH was examined theoretically by computational methods with results that were verified experimentally. This study reveals that under aerobic condition, complexes with VO3+ (1,2) and V2O34+ (3, 4) motifs were formed in protic CH3OH and neutral CHCl3 solvent respectively while the formation of complexes (5–14) with VO2+ motif required protic CH3OH solvent and higher pH (≥ 7). Interconversion of VO3+, V2O34+ and VO2+ motifs are associated with specific acid-base equilibria, substantiated by 51V NMR titrations. Complexes containing these three motifs exhibited promising in vitro anticancer activity in SiHa cervical cancer cells without affecting healthy cells; among them complexes (5–14) with VO2+ motif are more potent. A detailed systematic mechanistic study was carried out, utilizing the two most potent complexes 5 and 6 (IC50 = 13, 6 μM respectively), which indicates that cytotoxicity and anti-proliferative activity of these complexes are manifested through oxidative stress induced apoptotic pathways (caspase mediated).