含噻吩并[2,3-e][1,2,4]三氮唑并[4,3-c]嘧啶结构的芳基脲类化合物的合成及抗肿瘤活性研究

Synthesis and antitumor activities of arylureas bearing thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine moiety

目的设计并合成含噻吩并[2,3-e][1,2,4]三氮唑并[4,3-c]嘧啶结构的芳基脲类化合物,测试其抗肿瘤活性。方法采用杂合体策略,将1,2,4-三氮唑基团并入噻吩并嘧啶环的3,4位,得到噻吩并[2,3-e][1,2,4]三氮唑并[4,3-c]嘧啶骨架,在该骨架5位引入双芳基脲结构,同时对双芳基脲结构进一步修饰,得到目标化合物10a~10s。以3-氨基噻吩-2-甲酸甲酯为起始原料,经环合、氯代、取代、环合4步反应制得关键中间体5,中间体5再与中间体6进行Suzuki偶联反应得到关键中间体8,继而与取代的氨基甲酸苯酯9a~9s反应制得目标化合物10a~10s。采用MTT法评价其体外抗肿瘤活性。结果与结论共合成了19个未见文献报道的化合物,其结构经MS、^(1)H-NMR确证。化合物10j对PC-3和HCT-116细胞表现出较好的增殖抑制活性,其IC_(50)值分别为1.88μmol·L^(-1)和1.92μmol·L^(-1);对A549细胞表现出中等强度的增殖抑制活性,IC_(50)值为13.47μmol·L^(-1),并且对HCT-116细胞株的抗增殖活性优于阳性药GDC-0941。

Using a hybrid strategy,the 1,2,4-triazolyl group was incorporated into the 3,4-position of the thienopyrimidine ring to get a thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine skeleton.Accordingly,an arylurea moiety was introduced at 5-position of the skeleton,and 19 target compounds 10 a-10 s were obtained by further modification.With methyl 3-aminothiophene-2-carboxylate as the starting material,the key intermediate 5 was prepared through four steps of cyclization,chlorination,substitution and cyclization.Intermediate 5 was then subjected to Suzuki coupling reaction with intermediate 6 to give the key intermediate 8,which was then reacted with the substituted phenyl carbamates 9 a-9 s to obtain the target compounds 10 a-10 s.The structures of the target compounds were confirmed by MS and ^(1)H-NMR.Their in vitro antitumor activities were evaluated by MTT assay.The results showed that compound 10 j exhibited excellent anti-proliferation activity against PC-3 and HCT-116 cell lines,with IC_(50) values of 1.88μmol·L^(-1) and 1.92μmol·L^(-1),respectively,and moderate activity against A594 cell line with IC_(50) value of 13.47μmol·L^(-1).Compound 10 j exhibited more potent cytotoxicity against HCT-116 cell line than the positive drug GDC-0941.