Synthesis, DNA/BSA Interactions And Studies On Anticancer Activities Of Unsymmetrical Oxovanadium Complexes

Recently, a great deal of attention has been paid to the oxovanadium complexes due to their vital roles in a variety of biochemical processes, particularly after the discovery of its involvement in anticancer activities. Oxovanadium complexes, especially with biological ligands, exhibit better potent antitumor activity, DNA binding and DNA-photocleavage activities. However, there is still less information focused on the antitumor activities mechanism of oxovanadium complexes. In order to study that, we have synthesized a series of L-amino acid oxovanadium complexes and studied their antitumor activities by using molecular biology method. The main work is as follows:1. A series of oxovandium complexes with L-amino acid Schiff ligands/5-aminoorotic acid Schiff base ligands and auxiliary ligand 1,10-phen have been synthesized and characterized by using elemental analysis, FT-IR., 1HNMR, ESI-MS and electrical conductivity.2. The interactions of these complexes with CT-DNA have been investigated by UV-Vis absorption, fluorescence spectra and viscosity measurements. Their photocleavage reactions with pBR 322 supercoiled plasmid DNA were were studied by gel electrophoresis. All of the complexes show strong interactions with calf thymus DNA(CT-DNA) through an intercalative model and can efficiently cleave pBR322 DNA. The ability of cleavage is related to the compounds can generate hydroxyl radical at the present of H2O2. In addition, the antioxidant ability of these compounds have also been detected by using the Fenton system. All the selected compounds could scavenge hydroxyl radical(·OH) at a low range of concentrations, and its variation trend is the same as previous photocleavage reactions experiment. It should be noted that the ability of scavenging hydroxyl radical was decreased at a very high range of concentrations. This may owing to the complexes could occur selfoxidation-reduction reaction at a very high concentration of the compounds, and then decreased the scavenging rates.The interaction of these complexes with BSA was also studied. The results indicate that there is a strong interaction between the BSA protein and the oxovanadium complexes. It also suggested that these compounds could easily be stored in the proteins.3. The antitumor activities of these oxovanadium complexes were detected by using MTT assay. The results showed that all the oxovanadium complexes exhibited good cytotoxic activities against Hela and HepG2 cell lines, and some of these compounds even better than that of cis-platinum under the same condition. To understand the antitumor mechanism of the oxovanadium complexes, the apoptosis and cell cyclewere detected by flow cytometry(FCM). The results show that oxovanadium complexes can induce apoptotic in Hela and HepG2 tumor cells and block the cell cycle in G2/M and have a centration dependent. The western blot was used to study the expression of protein p53, bax and bcl-2. The results show that Hela cells exposed to complex for 48 h showed dose-dependent in the expression levels of p53, Bcl-2 and Bax. The expression of Bcl-2 and Bax may be incuced by p53 accumulation which triggered by DNA-damaging. This demonstrated that the effects of complex on expression of p53 could induce a down-regulation of Bcl-2 and up-regulation Bax, which acted as an important pathway for their growth inhibition on Hela cells. And so, the above induction of G2/M-phase arrest by up-regulation of p53 implied that the mechanism of cell apoptosis induced by oxovanadium complexes may be reduced the ability of Bcl-2 to bind to Bax and then enhanced the translocation of Bax from cytosol to mitochondria, which can lead to increase the susceptibility of the cells to apoptosis. In given condition, the mechanisms of apoptosis in tumour cells may involve the mitochondrial pathway. To fully understand the mechanism involved in the induction of apoptosis by oxovanadium complexes, further investigation will be needed to be carried out.