Synthesis and antiproliferative activity of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety

  • Eur J Med Chem. 2018 Jan 1:143:266-275. doi: 10.1016/j.ejmech.2017.11.034.
Qidong Tang  1 ,  Yongli Duan  2 ,  Linxiao Wang  2 ,  Min Wang  2 ,  Yiqiang Ouyang  2 ,  Caolin Wang  2 ,  Han Mei  2 ,  Sheng Tang  2 ,  Yinhua Xiong  2 ,  Pengwu Zheng  2 ,  Ping Gong  3 ,  Wufu Zhu  4
Affiliations
  • 1. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
  • 2. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
  • 3. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, 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].
PMID: 29197731 DOI: 10.1016/j.ejmech.2017.11.034
Abstract

A series of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety were synthesized, and evaluated for their antiproliferative activity against four Cancer cell lines (HT-29, A549, H460, and U87MG) and six tyrosine kinases (c-Met, Flt-3, PDGFR-β, VEGFR-2, EGFR, and c-Kit) inhibitory activities in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 32 showing Flt-3/c-Met IC50 value of 1.16/1.92 nM. Structure-activity relationship studies indicated that the hydrogen atom served as R1 group was benefited to the potency, and mono-electron-withdrawing groups (mono-EWGs) on the phenyl ring (such as R3 = 4-F) showed a higher preference for antiproliferative activity.

Keywords
1,8-Naphthyridin-2-one; Antiproliferative activity; Flt-3; Pyrrolo[2,3-b]pyridine derivatives; Synthesis; c-Met.