有机化学 ›› 2022, Vol. 42 ›› Issue (11): 3853-3862.DOI: 10.6023/cjoc202205028 上一篇    下一篇

研究论文

含噻唑结构的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究

戴洪林a,b, 司晓杰a,b, 池玲玲a,b, 王浩a,b, 高潮a,b, 汪正捷a,b, 刘丽敏a,b, 马家婕a,b, 于富强a,b, 刘宏民a,b,c,d,*(), 可钰a,b,c,d,*(), 张秋荣a,b,c,d,*()   

  1. a郑州大学药学院 郑州 45001
    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:2022-05-18 修回日期:2022-06-28 发布日期:2022-07-05
  • 通讯作者: 刘宏民, 可钰, 张秋荣
  • 基金资助:
    国家自然科学基金(U1904163)

Synthesis and Antitumor Activity Evaluation of 2,4,6-Trisubstituted Quinazoline Derivatives Containing Thiazole Structure

Honglin Daia,b, Xiaojie Sia,b, Lingling Chia,b, Hao Wanga,b, Chao Gaoa,b, Zhengjie Wanga,b, Limin Liua,b, Jiajie Maa,b, Fuqiang Yua,b, Hongmin Liua,b,c,d(), Yu Kea,b,c,d(), Qiurong Zhanga,b,c,d()   

  1. aSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
    bCollaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001
    cKey Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou 450001
    dState Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450052
  • Received:2022-05-18 Revised:2022-06-28 Published:2022-07-05
  • Contact: Hongmin Liu, Yu Ke, Qiurong Zhang
  • Supported by:
    National Natural Science Foundation of China(U1904163)

设计合成了一系列含有噻唑结构的2,4,6-三取代喹唑啉衍生物, 并测定了他们对PC-3(人前列腺癌细胞系)、H1975(人肺腺癌细胞系)、MGC-803(人胃癌细胞系)和A549(人非小细胞肺癌细胞系)四种人肿瘤细胞的抗增殖活性. 其中, 3-((2-(((2-氯噻唑-5-基)甲基)硫代)-6-甲氧基喹唑啉-4-基)氨基)苯甲氰(14i)是抗MGC-803细胞增殖活性最好的化合物, IC50为(4.54±0.32) μmol/L, 优于阳性对照5-氟尿嘧啶(5-FU) [(8.14±0.68) μmol/L], 其作用机理实验显示化合物14i具有抑制MGC-803细胞克隆增殖和迁移, 以及可诱导细胞凋亡的作用, 并且可以将MGC-803细胞周期阻滞在DNA合成后期/有丝分裂期(G2/M). 这些结果表明, 化合物14i可作为一种潜在的抗肿瘤药物.

关键词: 噻唑, 喹唑啉, 抗肿瘤活性, 合成

A series of 2,4,6-trisubstituted quinazoline derivatives containing thiazole group were designed and synthesized, and their antiproliferative activities against human tumor cell lines (PC-3, H1975, MGC-803 and A549) were determined. 3-((2-(((2-chlorothiazol-5-yl)methyl)thio)-6-methoxyquinazolin-4-yl)amino)benzonitrile (14i) was identified as the most potent compound in antiproliferation against MGC-803 cells, with the value was (4.54±0.32) μmol/L, which was better than the positive control 5-fluorouracil (5-FU) [(8.14±0.68) μmol/L]. Further mechanistic studies showed that compound 14i could inhibit the clonal proliferation and migration of MGC-803 cells. In addition, compound 14i could induce apoptosis of MGC-803 cells and arrest the cell cycle at late period of DNA synthesis/mitotic phase (G2/M) phase. These results indicated that compound 14i could as a potential antitumor drug.

Key words: thiazole, quinazoline, antitumor activity, synthesis