有机化学 ›› 2019, Vol. 39 ›› Issue (10): 2875-2881.DOI: 10.6023/cjoc201903062 上一篇    下一篇

研究论文

含脲砌块的4-氨基喹唑啉衍生物的设计、合成及抗肿瘤活性研究

李二冬ad, 孟娅琪ad, 张路野ab, 张洋ab, 王继宽ab, 张丹青ab, 宋攀攀bc, 辛景超bc, 栗娜bc, 郑甲信ad, 可钰abcd*(), 刘宏民abcd*(), 张秋荣abcd*()   

  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 河南省药物质量评价重点实验室 郑州 450001
    d 教育部药物制备关键技术重点实验室 郑州 450001
  • 收稿日期:2019-03-27 修回日期:2019-05-20 出版日期:2019-10-25 发布日期:2019-06-03
  • 通讯作者: 可钰,刘宏民,张秋荣 E-mail:ky@zzu.edu.cn;liuhm@zzu.edu.cn;zqr409@yeah.net
  • 基金资助:
    国家自然科学基金(81430085);河南省自然科学基金(182300410321);河南省科技厅(No. 182102310249)

Design, Synthesis and Antitumor Activity Evaluation of 4-Aminoquinazoline Derivatives Containing Urea Moiety

Li, Erdongad, Meng, Yaqiad, Zhang, Luyeab, Zhang, Yangab, Wang, Jikuanab, Zhang, Danqingab, Song, Panpanbc, Xin, Jingchaobc, Li, Nabc, Zheng, Jiaxinad, Ke, Yuabcd*(), Liu, Hongminabcd*(), Zhang, Qiurongabcd*()   

  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 Henan Province for Drug Quality and Evaluation, Zhengzhou 450001
    d Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education, Zhengzhou 450001
  • Received:2019-03-27 Revised:2019-05-20 Online:2019-10-25 Published:2019-06-03
  • Contact: Ke, Yu,Liu, Hongmin,Zhang, Qiurong E-mail:ky@zzu.edu.cn;liuhm@zzu.edu.cn;zqr409@yeah.net
  • Supported by:
    Project supported by the National Natural Science Foundation of China(81430085);the Natural Science Foundation of Henan Province(182300410321);the Technology Department Project of Henan Province(No. 182102310249)

为了寻找新的具有靶向治疗作用的抗肿瘤药物, 设计并合成了一系列新型的含脲砌块的4-氨基喹唑啉类衍生物, 并采用噻唑蓝(MTT)法测定目标化合物对MCF-7(人乳腺癌细胞)、MGC-803(人胃癌细胞)、SW620(人结肠癌细胞)、A549(人肺癌细胞)四种肿瘤细胞的抗肿瘤活性. 结果显示大部分化合物具有较好的抗肿瘤活性, 其中2-((4-((3,4,5-三甲氧基苯基)-氨基)喹唑啉-2-基)-硫代)-N-((3,4,5-三甲氧基苯基)氨基甲酰基)乙酰胺(10p)对MGC-803、SW620和A549三种细胞显示出最好的抗肿瘤活性, IC50值分别为(7.02±0.46)、(6.00±0.78)和(7.04±1.11) μmol?L –1, 其抗肿瘤活性和阳性对照品吉非替尼相当. 分子对接结果显示, 化合物10p能与EGFR很好地结合, 有可能成为潜在的抗肿瘤药物.

关键词: 脲砌块, 4-氨基喹唑啉, 合成, 抗肿瘤活性

In order to find new anti-tumor drugs with targeted therapeutic effect, a series of novel 4-aminoquinazoline derivatives bearing urea moiety were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines of MCF-7, MGC-803, SW620 and A549 using methyl thiazolyl tetrazolium (MTT) assay. Most of the target compounds exhibited excellent anti-tumor activity against the four human tumor cell lines. Among them, 2-((4-((3,4,5-trimethoxyphenyl)- amino)quinazolin-2-yl)-thio)-N-((3,4,5-trimethoxyphenyl)carbamoyl)acetamide (10p) showed the best antitumor activity against MGC-803, SW620 and A549 cancer cell lines with IC50 values of (7.02±0.46), (6.00±0.78) and (7.04±1.11) μmol? L –1, respectively. Its activity was comparable to the positive control of gefitinib. Molecular docking showed that compound 10p could bind well with EGFR, suggesting that it could be a potential antitumor agent.

Key words: urea moiety, 4-aminoquinazoline, synthesis, antitumor activity