有机化学 ›› 2022, Vol. 42 ›› Issue (1): 249-256.DOI: 10.6023/cjoc202107026 上一篇    下一篇

所属专题: 有机氟化学虚拟合辑

研究论文

含三氟甲基的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究

汪正捷a,b, 戴洪林a,b, 司晓杰a,b, 高潮a,b, 刘丽敏a,b, 张路野a,b, 张洋a,b, 宋亚丹a,b, 赵培荣a,b,c, 郑甲信a,b, 可钰a,b,*(), 刘宏民a,b,c,d,*(), 张秋荣a,b,d,*()   

  1. a 郑州大学药学院 郑州 450001
    b 郑州大学 新药研究与安全评价协同创新中心 郑州 450001
    c 郑州大学 食管癌防治国家重点实验室 郑州 450052
    d 郑州大学 教育部药物制备关键技术重点实验室 郑州 450001
  • 收稿日期:2021-07-12 修回日期:2021-08-13 发布日期:2021-08-28
  • 通讯作者: 可钰, 刘宏民, 张秋荣
  • 基金资助:
    国家自然科学基金(U1904163); 国家蛋白质研究项目(2018YFE0195100); 省部共建食管癌防治国家重点实验室资助的开放基金(K2020000X)

Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl

Zhengjie Wanga,b, Honglin Daia,b, Xiaojie Sia,b, Chao Gaoa,b, Limin Liua,b, Luye Zhanga,b, Yang Zhanga,b, Yadan Songa,b, Peirong Zhaoa,b,c, Jiaxin Zhenga,b, Yu Kea,b(), Hongmin Liua,b,c,d(), Qiurong Zhanga,b,d()   

  1. a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
    b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001
    c State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052
    d Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001
  • Received:2021-07-12 Revised:2021-08-13 Published:2021-08-28
  • Contact: Yu Ke, Hongmin Liu, Qiurong Zhang
  • Supported by:
    National Natural Science Foundation of China(U1904163); National Key Research Program of Proteins(2018YFE0195100); Opening Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)

为了寻找高效低毒的抗肿瘤药物, 设计并合成了一系列新型的含三氟甲基基团的2,4,6-三取代喹唑啉喹唑啉类衍生物, 并采用噻唑蓝(MTT)比色法测定目标化合物对人前列腺癌细胞系(PC-3)、人乳腺癌细胞系(MCF-7)、人食管癌细胞系(Eca-109)、人胃癌细胞系(MGC-803)、人未分化胃癌细胞系(HGC-27)、人非小细胞肺癌细胞系(A549)和人非小细胞肺癌细胞系(H1975)的抗肿瘤活性. 结果显示部分化合物表现出中度至强效的抗肿瘤活性, 其中N-(3-溴苯基)-6-甲氧基-2-((4-(三氟甲基)苄基)硫代)喹唑啉-4-胺(16l)对PC-3细胞具有最好的抗肿瘤活性, IC50值为(2.22±0.15) μmol/L, 抗肿瘤活性明显优于阳性对照品吉非替尼. 此外, 化合物16l对PC-3细胞以浓度依赖与时间依赖的方式诱导其凋亡.

关键词: 三氟甲基, 喹唑啉, 合成, 抗肿瘤活性

In order to find efficient and low toxicity antitumor drugs, a series of novel 2,4,6-trisubstituted quinazoline derivatives containing trifluoromethyl were synthesized and evaluated for their antitumor activities against human cancer cell lines (PC-3, MCF-7, Eca-109, MGC-803, HGC-27, A549, H1975) by using methyl thiazolyl tetrazolium (MTT) assay. Most of compounds exerted moderate to excellent antitumor activity against seven human cancer cells. Among them, N-(3-bromophenyl)-6-methoxy-2-((4-(trifluoromethyl)benzyl)thio)quinazolin-4-amine (16l) showed the best antitumor activity against PC-3 cancer cell line, with the IC50 values of (2.22±0.15) μmol/L, which was better than the positive control of gefitinib. At the same time, and compound 16l could dose-dependently and time-dependently induce PC-3 cells apoptosis.

Key words: trifluoromethyl, quinazoline, synthesis, antitumor activity