含1-4-二-(4-氟苯)甲基哌嗪官能团的1,2,3-三氮唑衍生物的合成及抗肿瘤活性研究

摘要

Eight novel 1,2,3-triazole derivatives were prepared via three steps starting from[1-bi-(4-fluorophenyl)-methyl] piperazine,benzyl bromides,propargyl bromide and sodium azide,using a very simple catalytic system composed of 5 mo1％ copper(Ⅱ)bromide and DMF-H2O(1 ∶ 1)as solvent at 70℃ for 4h with a yield(43 ～83％).The structures of the new compounds were characterized by IR,MS,1H NMR,and 13C NMR.The bioactive assay for the newly prepared compounds manifested that six compounds exhibited a distinct inhibitory activity against CDC25B.Thereinto,compounds 4 (b,c,g)exhibited excellent inhibitory activity against Leukemia HL-60 and Lung cancer A-549 cell(Leukemia HL-60 cell:IC50 value up to 10.99μM,8.82μM,and 15.23μM respectively.Lung cancer A-549 cell:IC50 value up to 21.11 μM,13.51 μM and 16.26μM respectively).At the same time,compound 4c exhibited an obvious inhibitory activity against Liver cancer SMMC-7721 cell with a IC50 value of 16.26 μM.%以1-[二-(4-氟苯)甲基]哌嗪、苄溴、溴丙炔及NaN3为原料,应用5 mol％的CuBr2或CuI为催化剂,DMF-H20为溶剂,在70℃反应4h以43～ 83％的收率制得了8个含有1-[4-二-(4-氟苯)甲基]哌嗪基官能团的-1,2,3-三氮唑衍生物4(a ～h).合成的8个目标化合物通过熔点测定和质谱、红外光谱、核磁共振氢谱分析对其结构进行确证.经体外抗肿瘤活性测试表明有6个化合物对CDC25b具有较好的抑制活性,其抑制率为78～ 97％,IC50可为16.91 ～ 11.55μM.化合物4b,4c及4g对白血病HL-60肿瘤细胞生长的抑制率分别为98％,97％和93％,IC50分别为10.99 μM,8.82 μM和15.23μM;对肺癌A-549肿瘤细胞生长的抑制率分别可达90％,88％和73％,IC50可分别达21.11μM,13.51μM和16.12μM.化合物4c对肝癌SMMC-7721细胞生长的抑制率可高达91％,IC50可达16.26μM.