Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents

  • Bioorg Med Chem Lett. 2018 Feb 1;28(3):254-259. doi: 10.1016/j.bmcl.2017.12.063.
Yongli Duan  1 ,  Shan Xu  1 ,  Hehua Xiong  1 ,  Linxiao Wang  1 ,  Bingbing Zhao  1 ,  Ping Wang  1 ,  Caolin Wang  1 ,  Yiqing Peng  1 ,  Shifan Cai  1 ,  Rong Luo  2 ,  Pengwu Zheng  3 ,  Qidong Tang  4
Affiliations
  • 1. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
  • 2. Jiangxi Province Institute of Materia Medica, Nanchang 330000, PR China.
  • 3. 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].
  • 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: 29317165 DOI: 10.1016/j.bmcl.2017.12.063
Abstract

A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 Cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61 nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2 = 4-F) was benefited to the potency.

Keywords
1,8-Naphthyridinone; 4-Phenoxypyridine derivatives; Antiproliferative activity; Flt-3; Synthesis; c-Met.