Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety

  • Eur J Med Chem. 2018 Oct 5:158:201-213. doi: 10.1016/j.ejmech.2018.08.066.
Qidong Tang  1 ,  Yongli Duan  2 ,  Hehua Xiong  2 ,  Ting Chen  2 ,  Zhen Xiao  2 ,  Linxiao Wang  2 ,  Yueyue Xiao  2 ,  Shunmin Huang  2 ,  Yinhua Xiong  2 ,  Wufu Zhu  2 ,  Ping Gong  3 ,  Pengwu Zheng  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: 30216852 DOI: 10.1016/j.ejmech.2018.08.066
Abstract

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three Cancer cell lines (A549, HepG2 and MCF-7) and several compounds (25, 27, 33, 37, 41, 43, 49 and 53) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC50 c-Met = 2.36 nM) showed excellent activity against A549, HepG2 and MCF-7 cell lines with IC50 values of 0.23 μM, 0.42 μM and 0.21 μM, respectively, which was 1.5-2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against FLT3, PDGFR-α, PDGFR-β, c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R2 = F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, Apoptosis (acridine orange staining), Apoptosis result analyzing and molecular docking.

Keywords
Antiproliferative activity; Quinoline derivatives; Synthesis; c-Met.