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2022 , Vol. 42 >Issue 11: 3824 - 3834

DOI: https://doi.org/10.6023/cjoc202205048

研究论文

新型2,4,6-三取代嘧啶衍生物的合成及抗增殖活性评价

  • 高潮 ,
  • 张玉桐 ,
  • 池玲玲 ,
  • 王浩 ,
  • 马家婕 ,
  • 毕梦鑫 ,
  • 戴洪林 ,
  • 司晓杰 ,
  • 刘丽敏 ,
  • 张洋 ,
  • 郑甲信 ,
  • 可钰 ,
  • 刘宏民 ,
  • 张秋荣
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  • 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和药物质量与评价中心 郑州450001
    c郑州大学 省部共建食管癌防治国家重点实验室 郑州 450052
    d教育部药物制备关键技术重点实验室 郑州 450001

收稿日期: 2022-05-28

  修回日期: 2022-06-27

  网络出版日期: 2022-07-14

基金资助

国家自然科学基金(U21A20416); 省部共建食管癌防治国家重点实验室开放基金(K2020000X)

收起

Synthesis and Antiproliferative Activity Evaluation of Novel 2,4,6-Trisubstituted Pyrimidine Derivatives

  • Chao Gao ,
  • Yutong Zhang ,
  • Lingling Chi ,
  • Hao Wang ,
  • Jiajie Ma ,
  • Mengxin Bi ,
  • Honglin Dai ,
  • Xiaojie Si ,
  • Limin Liu ,
  • Yang Zhang ,
  • Jiaxin Zheng ,
  • Yu Ke ,
  • Hongmin Liu ,
  • Qiurong Zhang
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  • aSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
    bCollaborative Innovation Center of New Drug Research & Quality and Safety Evaluation, Zhengzhou 450001
    cState Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052
    dKey Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001
*E-mail: ;
;

Received date: 2022-05-28

  Revised date: 2022-06-27

  Online published: 2022-07-14

Supported by

National Natural Science Foundation of China(U21A20416); Opening Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)

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摘要

为了寻找新型高效的抗肿瘤药物, 设计合成了一系列2,4,6-三取代嘧啶衍生物, 并采用噻唑蓝(MTT)法测定目标化合物对PC-3(人前列腺癌细胞)、MGC-803(人胃癌细胞)、MCF-7(人乳腺癌细胞)、HGC-27(人未分化胃癌细胞)四种人肿瘤细胞的抗增殖活性. 结果显示大部分化合物表现出中度至强效的抗增殖活性, 其中N-(3-(2-((4-((1,3,4-噻二唑-2-基)硫代)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺基)苯基)丙烯酰胺(19q)对PC-3细胞具有最好的抑制活性, IC50值为(0.87±0.15) μmol•L－1, 抗肿瘤活性明显优于阳性对照5-氟尿嘧啶. 进一步抗肿瘤机制研究表明, 化合物19q可以诱导PC-3细胞凋亡. 此外, 化合物19q可能是通过下调抗凋亡蛋白Bcl-2的表达, 上调促凋亡蛋白Bax和p53的表达而发挥抗肿瘤作用.

关键词： 嘧啶衍生物; 合成; 抗增殖活性

本文引用格式

高潮 , 张玉桐 , 池玲玲 , 王浩 , 马家婕 , 毕梦鑫 , 戴洪林 , 司晓杰 , 刘丽敏 , 张洋 , 郑甲信 , 可钰 , 刘宏民 , 张秋荣 . 新型2,4,6-三取代嘧啶衍生物的合成及抗增殖活性评价[J]. 有机化学, 2022 , 42(11) : 3824 -3834 . DOI: 10.6023/cjoc202205048

Abstract

In order to find new and efficient anti-tumor drugs, a series of 2,4,6-trisubstituted pyrimidine derivatives were designed and synthesized, and the antiproliferative activities were evaluated against four cancer cell lines of PC-3 (human prostate cancer cells), MGC-803 (human gastric cancer cells), MCF-7 (human breast cancer cells) and HGC-27 (human gastric carcinoma cell line) using methyl thiazolyl tetrazolium (MTT) assay. The results showed that most of the compounds exhibited moderate to potent antiproliferative activities against the four human tumor cell lines, among which N-(3-(2-((4-((1,3,4-thiadiazol-2-yl)thio)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamido)phenyl)acrylamide (19q) had the best inhibitory activity against PC-3 cells with IC50 value of (0.87±0.15) μmol•L－1, the antitumor activity was significantly better than the positive control 5-fluorouracil. Further anti-tumor mechanism studies showed that compound 19q could induce apoptosis in PC-3 cells. In addition, compound 19q might play an anti-tumor effect by down-regulating the expression of anti-apoptotic protein Bcl-2 and up-regulating the expression of pro-apoptotic proteins Bax and p53.

Key words： pyrimidine derivatives; synthesis; antiproliferative activity

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