Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety as potential antitumor inhibitor

  • Bioorg Med Chem Lett. 2020 Jan 15;30(2):126848. doi: 10.1016/j.bmcl.2019.126848.
Huimin Liu  1 ,  Yongli Duan  2 ,  Hehua Xiong  3 ,  Jianqing Zhang  3 ,  Shunmin Huang  3 ,  Ting Chen  3 ,  Pengwu Zheng  4 ,  Qidong Tang  5
Affiliations
  • 1. School of Perfume and Aroma Technology, Shanghai Institute of Technology; Engineering Research Center of Perfume & Aroma and Cosmetics of Ministry of Education, Shanghai 201418, PR China.
  • 2. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China; School of Optoelectronic Science and Engineering, University of Electronic Science and Technology of China (UESTC), Chengdu 610054, PR China.
  • 3. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
  • 4. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: [email protected].
  • 5. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: [email protected].
PMID: 31836443 DOI: 10.1016/j.bmcl.2019.126848
Abstract

A series of pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three Cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC50 = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-β and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R2 = F) on R, R1 and R2, respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking.

Keywords
4-Oxoquinoline; Anti-proliferative activity; Pyrrolo[2,3-b]pyridine derivatives; Synthesis; c-Met.