New mixed ligand oxidovanadium(IV) complexes: Solution behavior, protein interaction and cytotoxicity

Herein we report the synthesis of five new mononuclear mixed ligand oxidovanadium(IV) complexes [(VO)-O-IV(L1-3) (L-NN)] (1-5) with tridentate O,N,O-donor aroylhydrazones as main ligand (H2L1-3) and N,N-chelating 2,2 ' - bipyridine (bipy) and 1,10-phenanthroline (phen) as co-ligand (L-NN). The complexes were characterized by elemental and thermogravimetric analysis (TGA), IR, UV-vis, and electron paramagnetic resonance (EPR) spectroscopy, electrospray ionization-mass spectrometry (ESI-MS) and cyclic voltammetry (CV). The structure of 1-5 was confirmed by single crystal X-ray analysis and also optimized by density functional theory (DFT) methods. At physiological pH an equilibrium [(VO)-O-IV(L1-3)(L-NN)] + H2O ? [(VO)-O-IV(L1-3)(H2O)] + L-NN, shifted towards left, is established, with water molecule that could be replaced by the biomolecules of the organism. The studies on the interaction with two proteins, lysozyme (Lyz) chosen as a representative model of a small protein, and human serum albumin (HSA) show that two types of binding are possible: a non-covalent binding through the accessible residues on protein surface with [(VO)-O-IV(L1-3)(L-NN)] keeping its octahedral structure, and a covalent binding upon the replacement of water in [(VO)-O-IV(L1-3)(H2O)] with His-N donors to form (VO)-O-IV(L1-3)(HSA). In vitro cytotoxicity of ligands and complexes were screened against human cervical cancer (HeLa) (IC50 = 7.39-15.13 mu M), colon cancer (HT-29) (IC50 = 11.04-28.20 mu M) and mouse embryonic fibroblast (NIH-3T3) cell lines (IC50 = 62.22-87.75 mu M) by MTT assay. Particularly, 5 showed higher cytotoxicity than cisplatin and cyclophosphamide, with an IC50 of 7.39 +/- 1.21 mu M and 11.04 +/- 0.29 mu M against HeLa and HT-29.