有机化学 ›› 2021, Vol. 41 ›› Issue (1): 267-275.DOI: 10.6023/cjo202006054 上一篇    下一篇

研究论文

新型吲哚-嘧啶联芳类化合物的设计、合成及抗肿瘤活性研究

张丹青a,b, 柳旭a,b, 庞晓静a,b, 刘宏民a,b,c,*(), 张秋荣a,b,c,*()   

  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 教育部药物制备关键技术重点实验室 郑州 450001
  • 收稿日期:2020-06-26 修回日期:2020-08-04 发布日期:2020-09-15
  • 通讯作者: 刘宏民, 张秋荣
  • 作者简介:
    * Corresponding authors. E-mail: ;
    † 作者对文章贡献一致(The authors contributed equally to this work).
  • 基金资助:
    国家自然科学基金(U1904163); 蛋白关键研究项目(2018YFE0195100); 食管癌防治国家重点实验室资助的开放基金(K2020000X)

Design, Synthesis and Anticancer Activity Studies of Novel Indole-Pyrimidine Biaryl Derivatives

Danqing Zhanga,b, Xu Liua,b, Xiaojing Panga,b, Hongmin Liua,b,c,*(), Qiurong Zhanga,b,c,*()   

  1. a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
    b Co-Innovation Center of Henan Province for New Drug and Preclinical Safety, Zhengzhou 450001
    3 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001
  • Received:2020-06-26 Revised:2020-08-04 Published:2020-09-15
  • Contact: Hongmin Liu, Qiurong Zhang
  • Supported by:
    the National Natural Science Foundation of China(U1904163); the Key Research Program of Proteins(2018YFE0195100); the Opening Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)

设计合成了一系列新型的吲哚-嘧啶联芳类化合物, 并评估了它们对组蛋白去甲基化酶(LSD1)的抑制活性和5种肿瘤细胞系(MGC-803, PC-3, EC-109, PC-12和MCF-7)的抗增殖活性. 探讨了22个新型吲哚-嘧啶联芳类骨架衍生物的主要构效关系. 在这些化合物中, 1-(4-(4-(1-甲基-1 H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)-2-((3,4,5-三甲氧基苯基)氨基) 乙-1-酮(6i)展示出了潜在的LSD1抑制活性(IC 50=1.03 µmol/L), 而1-(4-(4-(1-甲基-1 H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)-2-(间甲苯胺)乙-1-酮(6c), 2-((4-丁基苯基)氨基)-1-(4-(4-(1-甲基-1 H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)乙-1-酮(6f)和2-((3-氟苯基)氨基)-1-(4-(4-(1-甲基-1 H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)乙-1-酮(6k)对PC-3细胞显示出潜在的抗肿瘤活性. 其中活性最强的化合物6k的对PC-3细胞系IC 50值为2.75 µmol/L, 可作为生物活性片段和开发更有效抗肿瘤药物的靶点化合物.

关键词: 吲哚, 嘧啶, 联芳基, 抗肿瘤活性

A series of novel indole-pyrimidine biaryl derivatives were designed, synthesized and evaluated for inhibitory activity against Lysine Specific Demethylase 1 (LSD1) and antiproliferative activity against five selected cancer cell lines (MGC-803, PC-3, EC-109, PC-12 and MCF-7). The priliminary structure-activity relationship (SAR) for this indole-pyrimidine biaryl scaffold was explored with evaluation of 22 variants of the structural class. Among these analogues, compound 1-(4-(4-(1-methyl-1 H-indol-3-yl)pyrimidin-2-yl)piperazin-1-yl)-2-((3,4,5-trimethoxyphenyl)amino)ethan-1-one (6i) exhibited the potential inhibitory activity against LSD1 (IC 50=1.03 µmol/L), compounds 1-(4-(4-(1-methyl-1 H-indol- 3-yl)pyrimidin-2-yl)piperazin-1-yl)-2-(m-tolylamino)ethan-1-one (6c), 2-((4-butylphenyl)amino)-1-(4-(4-(1-methyl-1 H-indol- 3-yl)pyrimidin-2-yl)piperazin-1-yl)ethan-1-one (6f) and 2-((3-fluorophenyl)amino)-1-(4-(4-(1-methyl-1 H-indol-3-yl)pyri- midin-2-yl)piperazin-1-yl)ethan-1-one (6k) showed the potential inhibitory activity aginst PC-3 cells. Especially, compound6k exhibited the best antitumor activity (IC 50=2.75 µmol/L), which was served as bioactive fragment and hit compound for developing more potent antitumor agents.

Key words: indole, pyrimidine, biaryl, antitumor