Hydrolytically Stable Ti^IV-Hydrazone-Based Metallodrugs: Protein Interaction and Anticancer Potential

In this work, three titanium(IV) [Ti-IV(L1-3)(2)] (1-3) complexes have been reported using three different tridentate dibasic ONO donor hydrazone ligands, pyridine-4-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)-hydrazide (H2L1), furan-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)-hydrazide (H2L2), and thiophene-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)-hydrazide (H2L3) tethered with heterocyclic moieties. Elemental analysis, FT-IR, UV-vis, NMR, HR-ESI-MS, and single-crystal X-ray analysis have been used to characterize H2L1-3 and 1-3. In solid structures of 1-3, two ligand molecules with N2O4 donor sets give distorted octahedral geometries to the metal center. The aqueous stability of 1-3 was investigated and well correlated to their perceived pharmacological results. During the investigation, all three complexes were found to be hydrolytically stable in a 90% DMSO-d(6)/10% D2O (v/v) medium up to 48 h. Furthermore, the interaction of 1-3 with bovine serum albumin (BSA) was tested using fluorescence and absorption techniques. The complexes showed static quenching with a biomolecular quenching constant of K-q similar to 10(13) proposing a high affinity of complexes for BSA. Finally, the anticancer potential of 1-3 was tested against HeLa, A549, and NIH-3T3 cell lines. Among all, 1 with an IC50 value of 11.6 +/- 1.1 mu M against HeLa cells was found to be the most cytotoxic in the series. Furthermore, it has been found that the compounds induce an apoptotic mode of cell death, which is confirmed by the live cell confocal microscopy and flow cytometry techniques.