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有机化学
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有机化学 ›› 2023, Vol. 43 ›› Issue (2): 636-645.DOI: 10.6023/cjoc202207001 上一篇    下一篇

研究论文

作为FABP4/5抑制剂喹啉类化合物的设计合成与生物活性研究

高建飞a,c,†, 李瞬依b,†, 何玉龙c, 李英霞c, 王贺瑶b, 黄二芳a,*(), 胡春a,*()   

  1. a 沈阳药科大学教育部基于靶点的药物设计与研究重点实验室 沈阳 110015
    b 中国科学院上海药物研究所 上海 201203
    c 复旦大学药学院 上海 201203
  • 收稿日期:2022-07-02 修回日期:2022-09-14 发布日期:2022-11-07
  • 作者简介:
    †共同第一作者
  • 基金资助:
    国家自然科学基金(21342006); 教育部创新团队(IRT_14R36)

Design, Synthesis and Biological Evaluation of FABP4/5 Inhibitors Based on Quinoline Scaffold

Jianfei Gaoa,c,†, Shunyi Lib,†, Yulong Hec, Yingxia Lic, Heyao Wangb, Erfang Huanga(), Chun Hua()   

  1. a Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110015
    b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
    c School of Pharmacy, Fudan University, Shanghai 201203
  • Received:2022-07-02 Revised:2022-09-14 Published:2022-11-07
  • Contact: *E-mail: erfanghuang@syphu.edu.cn;chunhu@syphu.edu.cn
  • About author:
    †(The authors contributed equally to this work).
  • Supported by:
    National Natural Science Foundation of China(21342006); Program for Innovative Research Team of the Ministry of Education(IRT_14R36)

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以罗氏公司报道的FABP4/5双靶标抑制剂RO6806051和FABP4抑制剂XU17为先导化合物, 根据RO6806051/FABP5复合物和XU17/FABP4复合物晶体结构, 通过骨架融合策略设计并合成了20个以喹啉为母核的结构新颖FABP4/5双靶标小分子抑制剂, 其结构经核磁共振氢谱(1H NMR)、核磁共振碳谱(13C NMR)和高分辨质谱(HRMS)确证. 采用8-苯胺基萘-8-磺酸(1,8-ANS)底物探针置换法对所合成的目标化合物进行了活性测试, 活性结果显示, 2-(2-(6-氯-4-(2-氯苯基)喹啉-2-基]苯基)乙酸(11a)对FABP4/5表现出较强的抑制活性, 其在25 μmol/L浓度下对FABP4抑制率为88%, IC50为4.50 μmol/L; 对FABP5抑制率为73%, IC50为3.9 μmol/L.

关键词: FABP4/5抑制剂, 融合策略, 喹啉, 合成

Taking the dual FABP 4/5 inhibitor RO6806051 and FABP4 inhibitor XU17 as the lead compounds, twenty new quinoline derivatives as dual FABP4/5 inhibitors were designed and synthesized according to the reported RO6806051/FABP5 crystal complex and XU17/FABP4 crystal complex, then confirmed by 1H NMR, 13C NMR and high-resolution mass spectra (HRMS). All the target compounds were evaluated for their inhibitory activity against FABP4 and FABP5 via the 8-anilino- naphthalene-1-sulfonic acid (1,8-ANS) displacement assay. The results showed that the target compound 2-(2-(6-chloro- 4-(2-chlorophenyl)quinolin-2-yl)phenyl)acetic acid (11a) exhibited strong inhibitory activity against FABP4 (IC50: 4.50 μmol/L) and FABP5 (IC50: 3.90 μmol/L).

Key words: FABP4/5 inhibitors, fusion strategy, quinoline, synthesis