有机化学 ›› 2020, Vol. 40 ›› Issue (1): 162-174.DOI: 10.6023/cjoc201905043 上一篇    下一篇

研究论文

基于咔唑的单-/双-硫代碳酰腙衍生物的合成及Cdc25B/PTP1B抑制活性评价

李英俊a, 杨凯栋a, 靳焜b, 高立信c, 盛丽c, 刘雪洁a, 杨鸿境a, 林乐弟a, 李佳c   

  1. a 辽宁师范大学化学化工学院 辽宁大连 116029;
    b 大连理工大学精细化工国家重点实验室 辽宁大连 116012;
    c 中国科学院上海药物研究所 国家新药筛选中心 药物研究国家重点实验室 上海 201203
  • 收稿日期:2019-05-21 修回日期:2019-08-02 出版日期:2020-01-25 发布日期:2019-09-12
  • 通讯作者: 李英俊, 李佳 E-mail:chemlab.lnnu@163.com;jli@simm.ac.cn
  • 基金资助:
    辽宁省自然科学基金(No.20102126)资助项目.

Synthesis and Cdc25B/PTP1B Inhibitory Activity Evaluation of Novel Carbazole-Based Mono-/Bis-thiocarbohydrazone Derivatives

Li Yingjuna, Yang Kaidonga, Jin Kunb, Gao Lixinc, Sheng Lic, Liu Xuejiea, Yang Hongjinga, Lin Ledia, Li Jiac   

  1. a College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, Liaoning 116029;
    b State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, Liaoning 116012;
    c National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
  • Received:2019-05-21 Revised:2019-08-02 Online:2020-01-25 Published:2019-09-12
  • Supported by:
    Project supported by the Natural Science Foundation of Liaoning Province (No. 20102126).

合成了一系列新型的基于咔唑的单-/双-硫代碳酰腙衍生物.利用IR、1H NMR、13C NMR和元素分析对其进行了结构表征.评价了目标化合物对Cdc25B和PTP1B的抑制活性,讨论了其结构与活性的关系.实验结果显示,大部分目标化合物对Cdc25B和PTP1B表现出良好的抑制活性.其中,1,5-双[(9-戊基-3-咔唑基)亚甲基]硫代碳酰腙(4d)对Cdc25B的抑制活性最高,IC50为(0.23±0.02)μg/mL.1,5-双[(9-乙基-3-咔唑基)亚甲基]硫代碳酰腙(4a)对PTP1B的抑制活性最高,IC50为(1.00±0.16)μg/mL.对目标化合物4a4d进行分子对接研究和密度泛函理论(DFT)计算,结果表明,目标化合物4d4a分别进入到了Cdc25B和PTP1B酶的活性位点区域,有活性作用的主要是硫代碳酰腙和咔唑基团.

关键词: 硫代碳酰腙, 咔唑, 合成, Cdc25B和PTP1B抑制剂, 分子对接, DFT计算

A series of novel carbazole-based mono-/bis-thiocarbohydrazone derivatives were synthesized. Their structures were characterized by IR, 1H NMR, 13C NMR spectra and elemental analysis. The inhibitory activities of the target compounds against Cdc25B/PTP1B were evaluated, and the relationship between structure and activity was discussed. The results showed that most of the target compounds had good inhibitory activity against Cdc25B and PTP1B. Among them, 1,5-bis[(9-pentyl-3-carbazolyl)methylene]thiocarbohydrazone (4d) had the highest inhibitory activity against Cdc25B with IC50=(0.23±0.02) μg/mL, and 1,5-bis[(9-ethyl-3-carbazolyl)methylene]thiocarbohydrazone (4a) had the highest inhibitory activity against PTP1B with IC50=(1.00±0.16) μg/mL. Molecular docking and density functional theory (DFT) calculations of the target compounds 4a and 4d were performed. Molecular docking results indicated that the target compounds 4d and 4a entered the active sites of Cdc25B and PTP1B enzymes, respectively, and thiocarbohydrazone and carbazole groups play the importent role of activity.

Key words: thiocarbohydrazone, carbazole, synthesis, Cdc25B and PTP1B inhibitor, molecular docking, DFT calculations