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研究论文

新型2,4,6,-取代嘧啶衍生物的设计、合成和抗肿瘤活性研究

张洋a,b, 张路野a,b, 王继宽a,b, 刘丽敏a,b, 王涛a,b, 栗娜a,b, 汪正捷a,b, 刘秀娟a,b, 陈雅欣a,b, 赵丹琳a,b, 郑甲信a,c, 单丽红a,b,c, 刘宏民a,b,c,d, 张秋荣a,b,c   

  1. a 郑州大学药学院 郑州 450001;
    b 新药创制与药物安全性评价河南省协同创新中心 郑州 450001;
    c 教育部药物关键制备技术重点实验室 郑州 450001;
    d 省部共建食管癌防治国家重点实验室, 郑州, 450052
  • 收稿日期:2020-07-29 修回日期:2020-08-26 出版日期:2030-01-01 发布日期:2020-08-31
  • 通讯作者: 单丽红, 刘宏民, 张秋荣 E-mail:shlh@zzu.edu.cn;liuhm@zzu.edu.cn;zqr409@yeah.net
  • 基金资助:
    国家自然科学基金(No.81773562),国家蛋白质研究项目(No.2018YFE0195100).省部共建食管癌防治国家重点实验室资助的开放基金(课题资助号:K2020000X)

Design, Synthesis and Antitumor Activity Evaluation of 2,4,6-substitute Pyrimidine Derivatives

Zhang Yanga,b, Zhang Luyea,b, Wang Jikuana,b, Liu Limina,b, Wang Taoa,b, Li Naa,b, Wang Zhengjiea,b, Liu Xiujuana,b, Chen Yaxina,b, Zhao Danlina,b, Zheng Jiaxina,c, Shan Lihonga,b,c, Liu Hongmina,b,c,d, Zhang Qiuronga,b,c   

  1. a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001;
    b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001;
    c Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001;
    d State Key Laboratory of Esophageal Cancer Prevention&Treatment, Zhengzhou 450052
  • Received:2020-07-29 Revised:2020-08-26 Online:2030-01-01 Published:2020-08-31
  • Supported by:
    Project supported by the National Natural Science Foundation of China (No. 81773562) and This work was supported by National Key Research Program of Proteins (No. 2018YFE0195100) and Openning fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment (No. K2020000X).

为了寻找高效的新型抗肿瘤药物,设计合成了一系列2,4,6-取代嘧啶衍生物,并使用噻唑蓝(MTT)法对四种人的肿瘤细胞SW-620(人结肠癌细胞),PC-3(人前列腺癌细胞),A549(人非小细胞肺癌细胞)和MGC-803(人胃癌细胞)进行了体外抗肿瘤活性研究。其中化合物5i,5o和5r对4种测试的癌细胞系显示出高的抗肿瘤增殖活性,特别是化合物5r具有最高的抑制活性,与阳性对照药5-氟尿嘧啶(5-Fu)相比,对SW-620的IC50值最低,为1.46μM。进一步机制研究表明,化合物5r诱导SW-620凋亡,使细胞周期阻滞在S期。分子对接揭示了化合物5r可以很好地结合EGFR的活性位点,化合物5r可能被认为是一种有前途的化合物,可用于进一步研究开发新的抗癌药物。

关键词: 嘧啶衍生物, 合成, 抗肿瘤活性, 细胞周期, 凋亡

With the expectation to find out novel and effective anti-tumor agents, a series of novel 2,4,6-substituted pyrimidine derivatives were synthesized and evaluated for their anti-tumor activity against four human cancer cells (SW-620, PC-3, A549 and MGC-803) using MTT assay. Among compounds, 5i, 5o and 5r displayed strong antiproliferative activity on 4 tested cancer cell lines, in particular, compound 5r did the highest inhibitive activity, and possessed the lowest IC50 value of 1.46 μM towards SW-620 cells compared to that of the positive reference drug 5-Fluorouracil(5-Fu). Further mechanism research showd compound 5r induced SW-620 apoptosis, arrested cell cycle at S phase. Molecular docking revealed that 5r can bind well to the active site of EGFR, and compound 5r may be considered as a promising compound amenable for further investigation for the development of new anticancer agents.

Key words: Pyrimidine derivatives, Synthesis, Antitumor activity, Cell cycle, Apoptosis