Efficient Arylation of 2,7-Naphthyridin-1(2H)-one with Diaryliodonium Salts and Discovery of a New Selective MET/AXL Kinase Inhibitor.
ACS Comb Sci, 2020/09/14;22(9):457-467.
Wang MS[1], Xu HC[1], Gong Y[1], Qu RY[1], Zhuo LS[1], Huang W[1]
Affiliations
PMID: 32589005DOI: 10.1021/acscombsci.0c00074
Impact factor: 3.903
Abstract
New 8-chloro-2-phenyl-2,7-naphthyridin-1(2H)-one building blocks bearing diverse substitutes on the 2-phenyl group were synthesized via an efficient diaryliodonium salt-based N-arylation strategy with the advantage of mild conditions, short reaction times, and high yields. A small combinatorial library of 8-amino substituted 2-phenyl-2,7-naphthyridin-1(2H)-one was further conveniently constructed based on the above chlorinated naphthyridinones and substituted aniline. Preliminary biochemical screening resulted in the discovery of the new 2,7-naphthyridone-based MET/AXL kinase inhibitors. More importantly, 17c (IC50,MET of 13.8 nM) or 17e (IC50,AXl of 17.2 nM) and 17i (IC50,AXl of 31.8 nM) can efficient selectively inhibit MET or AXL kinase, respectively, while commercial cabozantinib showed no selectivity. The further exploration of the 8-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one combinatorial library would significantly accelerate the discovery of more potent and selective inhibitors against diverse kinases.
Keywords: 2,7-naphthyridone; MET/AXL kinase inhibitor; N-arylation; diaryliodonium salts; selectivity
MeSH terms
Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Onium Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Receptor Protein-Tyrosine Kinases; Salts; Structure-Activity Relationship; Axl Receptor Tyrosine Kinase
More resources
EndNote: Download