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  

Design,Synthesis and Antitumor Activity Evaluation Research of Novel 2,4,6-Substituted Pyrimidine Derivatives

作　　者：张洋 张路野 王继宽 刘丽敏 王涛 栗娜 汪正捷 刘秀娟 陈雅欣 赵丹琳 郑甲信[1,3] 单丽红 刘宏民[1,2,3,4] 张秋荣 Zhang Yang;Zhang Luye;Wang Jikuana;Liu Limin;Wang Tao;Li Na;Wang Zhengjie;Liu Xiujuan;Chen Yaxin;Zhao Danlin;Zheng Jiaxin;Shan Lihong;Liu Hongmin;Zhang Qiurong(School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001;Collaborative Innovation Center of New Drug Research and Safety Evaluation,Zhengzhou 450001;Key Laboratory of Advanced Drug Preparation Technologies,Ministry of Education,Zhengzhou 450001;State Key Laboratory of Esophageal Cancer Prevention&Treatment,Zhengzhou 450052)

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协同创新中心,郑州450001 [3]教育部药物关键制备技术重点实验室,郑州450001 [4]食管癌防治国家重点实验室,郑州450052

出　　处：《有机化学》2021年第1期310-317,共8页Chinese Journal of Organic Chemistry

基　　金：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(No.K2020000X)资助项目.

摘　　要：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4种人的肿瘤细胞人结肠癌细胞(SW-620)、人前列腺癌细胞(PC-3)、人非小细胞肺癌细胞(A549)和人胃癌细胞(MGC-803)进行了体外抗肿瘤活性研究.其中化合物N-((4-乙基苯基)氨基甲酰基)-2-((4-(对甲苯基氨基)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺(5i),2-((4-((4-乙氧基苯基)氨基)-6-(三氟甲基)嘧啶-2-基)硫基)-N-((4-乙基苯基)氨基甲酰基)乙酰胺(5o)和N-((4-乙基苯基)氨基甲酰基)-2-((4-((4-甲氧基苯基)氨基)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺(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,对SW-620的IC_(50)值最低,为1.46μmol/L.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可以很好地结合表皮生长因子受体(EGFR)的活性位点,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.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(human colon cancer cells),PC-3(human prostate cancer cells),A549(Human non-small cell lung cancer cells),MGC-803(human gastric cancer cells)]using methyl thiazolyl tetrazolium(MTT)assay.Among tested compounds,N-((4-ethylphenyl)-carbamoyl)-2-((4-(p-tolylamino)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamide(5i),2-((4-((4-ethoxyphenyl)amino)-6-(tri-fluoromethyl)pyrimidin-2-yl)thio)-N-((4-ethylphenyl)carbamoyl)acetamide(5o)and N-((4-ethylphenyl)carbamoyl)-2-((4-((4-methoxyphenyl)amino)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamide(5r)displayed strong antiproliferative activity on 4 tested cancer cell lines.In particular,compound 5r has the highest inhibitive activity,and possessed the lowest IC_(50)value of 1.46μmol/L towards SW-620 cells.Further mechanism research shows that compound 5r induces SW-620 apoptosis,arrests cell cycle at S phase.Molecular docking reveals that 5r can bind well to the active site of epidermal growth factor receptor(EG-FR),and may be considered as a promising compound amenable for further investigation for the development of new anticancer agents.

关 键 词：嘧啶衍生物 合成 抗肿瘤活性 细胞周期 凋亡 

分 类 号：O626.41[理学—有机化学] TQ460.1[理学—化学]