Synthesis, in vitro cytotoxicity, and structure-activity relationships (SAR) of multidentate oxidovanadium(IV) complexes as anticancer agentsX

Multidentate oxidovanadium(IV) complexes with different geometric configurations [VO(ox)(bpy)(H2O)] 1, [VO(ox)(phen)(H2O)] 2, [VO(ida)(bpy)]center dot 2H(2)O 3, (phen)[VO(ida)(phen)]center dot 4H(2)O 4, and (Hphen)[VO(H2O) (nta)]center dot 2H(2)O 5 [ox = oxalic acid, bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, ida = iminodiacetic acid, nta = nitrilotriacetic acid] have been obtained from the reactions of oxidovanadium sulfate or vanadium pentoxide with oxalates, amino-polycarboxylates and N-heterocyclic ligands in neutral solution by the hydrothermal method, and have been fully characterized by elemental, thermogravimetric analyses and single crystal X-ray diffraction, as well as a wide range of spectroscopic techniques such as FT-IR, UV/Vis, NMR, ESI-MS. The anti-tumor properties of oxidovanadium compounds 1-5 were further evaluated in human HepG2 and SMMC-7721 hepatocellular carcinoma cell lines in vitro. The profiles of cytotoxicity, cell cycle distribution, as well as cell apoptosis upon test compound exposure, were determined by MTT and flow cytometry assays. Compound 2 exhibited a much higher anti-tumor activity than others. The IC50 values of 2 were 5.34 +/- 0.034 mu M and 29.07 +/- 0.017 mu M in SMMC-7721 and HepG2 cells after 48 h treatment, respectively. Furthermore, compound 2 could significantly arrest the cell cycle in the S and G(2)/M phases and further induce cell apoptosis in a dose-dependent manner. The structure-activity relationship (SAR) studies revealed that structural elements, for example, metal components, variations of coordination mode, labile water molecules, chelated ligands etc., probably exert an essential cooperative effect on the antitumor activity. In short, these findings not only provide an accessible model system to exploit V-based complexes as potential simple, safe and effective multifunctional antitumor agents, but also open up a rational approach to shed new light on the selection and optimization of ideal drug candidates.