有机化学 ›› 2022, Vol. 42 ›› Issue (1): 277-292.DOI: 10.6023/cjoc202106053 上一篇    下一篇

研究论文

以环丙烷限制构象的新型双酰胺的设计、合成、抗癌活性及计算分析

陈睿嘉a, 周聪a, 逄锡文a, 刘佳君b, 顾玉诚c, 刘建文b, 李忠a,*()   

  1. a 华东理工大学药学院 上海市化学生物学(芳香杂环)重点实验室 上海 200237
    b 华东理工大学药学院 生物反应器工程国家重点实验室&上海市新药设计重点实验室 上海 200237
    c 先正达Jealott′s Hill国际研发中心 英国 RG42 6EY
  • 收稿日期:2021-06-29 修回日期:2021-08-02 发布日期:2021-09-02
  • 通讯作者: 李忠
  • 基金资助:
    国家重点研发计划(2017YFD0200505)

Design, Synthesis, Anti-cancer Activities and Computational Analysis of Novel Diamides Conformationally Restricted by Cyclopropane

Ruijia Chena, Cong Zhoua, Xiwen Panga, Jiajun Liub, Yucheng Guc, Jianwen Liub, Zhong Lia()   

  1. a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237
    b State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237
    c Syngenta Jealott′s Hill International Research Centre, RG42 6EY, UK
  • Received:2021-06-29 Revised:2021-08-02 Published:2021-09-02
  • Contact: Zhong Li
  • Supported by:
    National Key Research Program of China(2017YFD0200505)

为了探索具有新型骨架的抗癌剂, 设计了一系列的以环丙烷限制构象的双酰胺类化合物. 大多数含有顺式环丙烷中心的外消旋体对四种肿瘤细胞系(MCF-7、BGC-823、HepG2和NCI-H460)具有良好的抑制活性. 其中, 消旋体顺式-N1-(2-甲基-4-(全氟丙-2-基)苯基)-N2-(4-苯氧基苄基)环丙烷-1,2-二羧酰胺(1-19)对MCF-7的IC50值为(8.38±0.67) mg•L–1, 显示出可进一步优化为抗癌先导物的潜力. 此外, 甾醇硫酸酯酶(steryl-sulfatase, STS)被PharmMapper预测为可能的靶标蛋白, 并由分子对接实验进行了验证.

关键词: 双酰胺, 环丙烷, 抗癌活性, 靶标预测, 分子对接

A series of diamides conformationally restricted by cyclopropane were designed and synthesized. Most of the racemates containing cis-cyclopropane possessed promising inhibitory activity against four cancer cell lines (MCF-7, BGC-823, HepG2 and NCI-H460). In particular, racemate cis-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)-N2-(4-phenoxy- benzyl)cyclopropane-1,2-dicarboxamide (1-19) showed the potential for further optimization as an anti-cancer lead with the IC50 value of (8.38±0.67) mg•L–1 on MCF-7. Moreover, steryl-sulfatase (STS) was predicated as the potential target protein and molecular docking was performed to explore the binding mode.

Key words: diamides, cyclopropane, anti-cancer activities, target prediction, docking