Design,Synthesis And Biological Activity Of 2-benzyloxy Bismuth(Ⅲ) Complexes

Objective:A series of 2-benzyloxybismuth（Ⅲ）complexes based on o-bromo benzyl ether derivatives are designed and synthesized.Meanwhile,their composition,structure and physicochemical properties are analyzed and characterized using modern characterization techniques.Moreover,the potential of the complexes for antibacterial and antitumor applications is investigated,and a reasonable structure-activity relationship is established.Methods:The o-bromo benzyl ether derivatives were synthesized by the Williamson ether synthesis method,while a series of 2-benzyloxybismuth（Ⅲ）complexes were synthesized by the lithium salt method and salt elimination method;the composition and structure of the complexes were investigated by modern analytical characterization techniques such as nuclear magnetic resonance,high resolution mass spectrometry and X-ray single crystal diffraction.The effects of the 2-benzyloxybismuth（Ⅲ）complex and its ligands on three Gram-positive bacteria,S.aureus,S.epidermidis and E.faecalis,and two Gram-positive bacteria,E.coli and P.aeruginosa,were tested by micro-broth dilution method using amoxicillin as positive control.The inhibition activity was determined using the agar diffusion method with S.aureus as the microbial model and the diameter of the inhibition circle.The antitumor activity of 2-benzyloxybismuth（Ⅲ）complexes and their ligands were tested against human lung cancer cells A549 and human gastric cancer cells SGC-7901 using the CCK-8 method with cisplatin as a positive control,and the cytotoxicity of these bismuth（Ⅲ）complexes against normal human hepatocytes L02 was evaluated.Results:Three o-bromo benzyl ether derivatives and six 2-benzyloxybismuth（Ⅲ）complexes were synthesized.The NMR data show that the chemical shifts of the benzyl hydrogen atoms in these bismuth（Ⅲ）complexes are different from those of the methyl hydrogen atoms in their ligands.The crystallographic data show that the bond lengths between the oxygen and bismuth atoms are in the following order:monoaryl bismuth（Ⅲ）dichloride<diaryl bismuth（Ⅲ）chloride<triaryl bismuth（Ⅲ）complexes;the coordination configurations are in the following order:triangular bipyramidal,tetragonal cone and octahedral configurations.Antibacterial activity studies showed that all the complexes inhibited bacterial growth in a concentration-dependent manner,whereas the ligands did not possess antibacterial activity,demonstrating that bismuth was an important factor in their antibacterial activity.Furthermore,these bismuth（Ⅲ）complexes were more effective against Gram-positive bacteria than Gram-negative bacteria.The results showed that the antibacterial activity was in the order of diaryl bismuth（Ⅲ）chloride complexes（Bi1 and Bi2）>monoaryl bismuth（Ⅲ）dichloride complexes（Bi3 and Bi4）>triaryl bismuth（Ⅲ）complexes（Bi5 and Bi6）.The selectivity index of Bi1 was found to be as high as 12.2 and these bismuth（Ⅲ）complexes could inhibit bacterial growth in a safe range.Antitumour activity studies showed that the ligands L1-L3 did not inhibit either solid tumour cells,while the six2-benzyloxy bismuth（Ⅲ）complexes inhibited both tumour cells better than the clinical drug cisplatin.Among them,Bi5 showed the best antitumour activity with IC₅₀ of 4.8±1.4μM and 5.3±1.0μM.The selectivity index（SI）of each complex was assessed by activity in human lung cancer cells A549 and human gastric cancer cells SGC-7901versus activity in L02 cells,showing that such hypervalent bismuth（Ⅲ）complexes are tumour selective.Conclusion:The influence of the type and number of ligands on the biological activity of the complexes was revealed.Based on the clog P value,"energy band gap"（Egap value）and crystallography data,it was clarified that the antibacterial/antitumor activity of such bismuth（Ⅲ）complexes depends on the synergistic effect of lipophilicity,coordination configuration and stability.