3,6-取代-1,2,4-三氮唑[3,4-a]酞嗪衍生物的合成和抗肿瘤活性评价  

Synthesis and Antitumor Activity Evaluation of 3,6-Substituted-1,2,4-triazolo[3,4-a]phthalazine Derivatives

作　　者：王超杰[1,2] 曹钦坡 杨慧[1,2] 宋攀攀[1,2] 薛登启[1,2] 崔飞[1,2] 顾一飞[1,2] 张孝松[1,2] 田亚楠[1] 张秋荣[1,2] 刘宏民[1,2] 

机构地区：[1]郑州大学药学院,郑州450001 [2]新药创制与药物安全性评价河南省协同创新中心,郑州450001

出　　处：《有机化学》2016年第7期1626-1635,共10页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.81430085);河南省科技厅基础(No.142300410328)资助项目~~

摘　　要：为了寻找高效、经济的抗肿瘤药物,以邻苯二甲酸酐为起始原料,经环合、氯代、取代和环合等反应,合成一系列的3,6-取代-1,2,4-三氮唑并[3,4-a]酞嗪衍生物.化合物的分子结构均经过~1H NMR、^(13)C NMR和HRMS确定,再利用四甲基偶氮唑盐(MTT)方法对合成的化合物在人类四种癌细胞MGC-803人胃癌细胞、EC-9706人食管癌细胞、Hela人宫颈癌细胞、MCF-7乳腺癌细胞进行抗肿瘤活性研究,其中化合物5d对EC-9706人食管癌细胞、Hela人宫颈癌细胞的抗肿瘤活性优于或相当于5-F尿嘧啶,其IC_(50)值分别为3.9和4.5μmol·L^(-1),通过初步作用机制研究,发现化合物5d能诱导EC-9706人食管癌细胞的早期凋亡,并将细胞周期阻断在G2/M阶段.With the aim of obtaining potential antitumor candidates with more efficiency and more economic value. A series of 3,6-substituted-1,2,4-triazolo[3,4-a]phthalazine derivatives were synthesized. The target products were obtained via cyclization, chlorination, substitution, cyclization, substituted with phthalic anhydride used as the starting material. The structures of target products are confirmed by 1H NMR, 13C NMR, HRMS. A series of 3,6-substituted-1,2,4-triazolo[3,4-a] phthalazine derivatives was evaluated for anticancer activity on four human cancer cell lines including EC-9706, HeLa and MCF-7 by MTT assay. Among them, compound 5d was more cytotoxic against EC-9706 and HeLa cell lines, with IC50 values ranging from 3.9 to 4.5 p.moloL-1, which are superior or comparable to 5-Fuorouracil. Flow cytometry analysis indicated that compound 5d induced the cellular early apoptosis and cell cycle arrest in G2/M phase in EC-9706.

关 键 词：三氮唑 酞嗪 抗肿瘤活性 凋亡 细胞周期 

分 类 号：O626[理学—有机化学]