高等学校化学学报 ›› 2019, Vol. 40 ›› Issue (12): 2502-2511.doi: 10.7503/cjcu20190544

• 有机化学 • 上一篇    下一篇

咪唑酮并[4,5-c]喹啉衍生物的合成及体外生物活性

李艳杰1,2,王恩思1,邵晓玮1,张兴民3,牛生秀1,杨丽娟1,武毅1,*()   

  1. 1. 吉林大学药学院, 长春 130012
    2. 长春中医药大学药学院, 长春 130117
    3. 北京富龙泰康生物技术有限公司, 北京 101111
  • 收稿日期:2019-10-21 出版日期:2019-12-04 发布日期:2019-12-04
  • 通讯作者: 武毅 E-mail:wuyi@jlu.edu.cn
  • 基金资助:
    吉林大学(中国)高新技术(集团)有限公司基金资助.

Synthesis and Biological Activity in vitro of Imidazo[4,5-c]quinoline Derivatives

Yanjie LI1,2,Ensi WANG1,Xiaowei SHAO1,Xingmin ZHANG3,Shengxiu NIU1,Lijuan YANG1,Yi WU1,*()   

  1. 1. College of Pharmacy, Jilin University, Changchun 130012, China
    2. College of Pharmacy, Changchun University of Traditional Chinese Medicine, Changchun 130117, China
    3. Beijing Foreland Pharma Biological Technology Co., Ltd., Beijing 101111, China
  • Received:2019-10-21 Online:2019-12-04 Published:2019-12-04
  • Contact: Yi WU E-mail:wuyi@jlu.edu.cn
  • Supported by:
    ? Supported by the Fund of Jilin University(China) Hi-Tech(Group) Co., Ltd..

摘要:

为了合成含有咪唑并喹啉结构骨架的高效PI3K/mTOR抑制剂, 以4-氯喹啉与苯胺的芳香亲核取代(SNAr)反应、 芳香二胺与三光气Traube缩合反应以及双芳基的Suzuki交叉偶联反应等为关键步骤, 合成了15个结构新颖的咪唑酮并[4,5-c]喹啉衍生物(8Aa~8Ae, 8Ba~8Be和8Ca~8Ce). 经核磁共振波谱(NMR)和高分辨质谱(HRMS)分析确证了关键中间体和目标化合物的结构. 采用ADP-Glo激酶试剂盒和TR-FRET mTOR试剂盒法检测了目标化合物对PI3K/mTOR的体外抑制活性, 发现所有化合物均表现出较强的活性.

关键词: 咪唑酮并喹啉, Traube反应, Suzuki反应, PI3K/mTOR双重抑制剂

Abstract:

In search of new and efficient PI3K/mTOR inhibitor based on the imidazoquinoline structural framework, 15 novel imidazo[4,5-c] quinoline were synthesized via SNAr reaction of 4-chloroquinoline with aniline, the Traube condensation reaction of aromatic diamine with triphosgene and the Suzuki coupling reaction of bromo-compounds with 3-quinoline boronic acid. The structures of the key intermediates and target compounds were confirmed by 1H NMR, 13C NMR and HRMS. Imidazo[4,5-c] quinolin analogues(8Aa—8Ae, 8Ba—8Be, 8Ca—8Ce) were evaluated for their in vitro activities against PI3Kα/mTOR by ADP-Glo kinase assay and TR-FRET assay, all compounds displayed strong activities.

Key words: Imidazoquinoline, Traube reaction, Suzuki reaction, PI3K/mTOR Dual inhibitor

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