Synthesis, DNA Interactions And Studies On Anticancer Activities In Vitro Of Fluoro-oxovanadium Complexes

A series of platinum complexes have been successively designed, developed andas the clinical efficacy of anti-cancer drugs since cisplatin was discovered andsuccessfully applied in clinic for the treatment of various malignant diseases. In recentyears, many researchers have drawn their attention to other non-platinum transitionmetal complexes owing to their good biological activities. Among them, the vanadiumand its compounds have attracted extensive interest for their wide biological effectssuch as antibacterial, antidiabetic, antimalarial, antiviral and so on. Previously, wereported that some Schiff bases oxovanadium complexes in which containing a largerconjugate aromatic flat structure showed a stronger ability of binding to DNA and thecapacity to cleavage plasmid DNA. Our previous results also indicated that thesecompounds present highly cytotoxic activities against tumor cell lines in vitro.In order to further explore the relationship between the structure and itsbiological activity of vanadium complexes, we have designed and synthesized a seriesof nine novel oxovanadium complexes, in which thiosemicarbazide derivatives and2-(2-hydroxybenzylideneamino) Schiff bases as primary ligands incorporated with theintroduction of electro-donating group(-OH) and electro-withdrawing group(-CF3) inortho-, meta-, para-position of imidazolinyl-phenanthroline auxiliary ligands. Themain work is as follows:1. The design is given priority to thiosemicarbazide derivatives as primary ligand,three hydroxy-substituted imidazole phenanthroline-based oxovanadium complexes[VO(hntdtsc)(HPIP)](1), [VO(hntdtsc)(m-HPIP)](2) and [VO(hntdtsc)(p-HPIP)](3)have been synthesized and characterized by using elemental analysis, nuclearmagnetic resonance(NMR), electrical conductivity and IR. The interaction of thesecomplexes with calf-thymus DNA(CT-DNA) was investigated using UV-Visabsorption, fluorescence spectra, viscosity measurements and thermal denaturation.Their cleavage reactions with p BR322 supercoiled plasmid DNA were studied by gelelectrophoresis. The results showed that these complexes interact with DNA byintercalation mode and can efficiently cleavage plasmid p BR322 DNA, the Kb valuesare as follows: 1 > 3 > 2. In addition, Fenton-like reaction experiment was employedto evaluate abilities of hydroxyl radical scavenger of these three complexes. AndMTT method was used to evaluate their anticancer activity in vitro against cervicalcancer cells(Ca Ski and Si Ha), leukemia cell(K562), hepatocellular carcinoma cell(Hep G2) and esophageal cancer cells(ECa9706 and ECa109). The results suggestedthat complexes 1-3 have a certain ability to scavenge hydroxyl free radical, andcomplex 1 show the best growth inhibition activity towards tested tumor cells with alowest IC50 value.2. Three novel fluoro-oxovanadium complexes [VO(hntdtsc)(CF3PIP)](1),[VO(hntdtsc)(m-CF3PIP)](2) and [VO(hntdtsc)(p-CF3PIP)](3) have been synthesizedand characterized by elemental analysis, IR, molar conductance, ESI-MS and 1HNMR. Spectroscopy and biological methods were used to discuss the electronic effectof the substituent and steric effect on biological activity. Moreover, Fenton’s reactionexperiment showed that complex 3 had the highest activity to scavenge hydroxylradical. In addition, the complexes 2 and 3 could induce significant early and lateapoptotic in ECa9706 and ECa109 tumor cells and block the cell cycle in G0/G1 and Sphases.3. In order to explore the effect of changing Schiff base ligands between thesecomplexes and their biological activity, three new fluoro-oxovanadium complexes[VO(Hbid)(CF3PIP)](1), [VO(Hbid)(m-CF3PIP)](2) and [VO(Hbid)(p-CF3PIP)](3),which contain a fluoro-phenanthroline derivatives and one Schiff base withintroducing a N-heterocyclic structure have been synthesized and characterized. Theinteraction of these complexes with calf-thymus DNA(CT-DNA) was investigatedusing various techniques. The results showed that the Kb values of these threeoxovanadium complexes containing(2-hydroxybenzylideneamino)isoindoline-1,3-dione were lower than that of containing thiosemicarbazide Schiffbase, which may be due to the(2-hydroxybenzylideneamino) isoindoline-1,3-dioneSchiff base with smaller conjugated aromatic system, led to a weaken π-π stackingbetween the inserted ligand and DNA base, which resulted to a decline in value of Kb.