Design and synthesis of 3,3'-biscoumarin-based c-Met inhibitors.
A library of biscoumarin-based c-Met inhibitors was synthesized, based on optimization of 3,3'-biscoumarin hit 3, which was identified as a non-ATP competitive inhibitor of c-Met from a diverse library of coumarin derivatives. Among these compounds, 38 and 40 not only showed potent enzyme activities with IC50 values of 107 nM and 30 nM, respectively, but also inhibited c-Met phosphorylation in BaF3/TPR-Met and EBC-1 cells.
Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, Republic of China. fjnan@simm.ac.cn.
Jimin
J
Xu
Jing
J
Ai
Sheng
S
Liu
Xia
X
Peng
Linqian
L
Yu
Meiyu
M
Geng
Fajun
F
Nan
D000255:Adenosine Triphosphate / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D014468:Umbelliferones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D003374:Coumarins; C000596984:N-(1-((7,8-dihydroxy-2-oxo-2H-chromen-3-yl)amino)-1-oxoheptan-2-yl)-7,8-dihydroxy-2-oxo-2H-chromene-3-carboxamide; C000596985:N-(1-((7,8-dihydroxy-2-oxo-2H-chromen-3-yl)amino)-1-oxooctan-2-yl)-7,8-dihydroxy-2-oxo-2H-chromene-3-carboxamide; D047428:Protein Kinase Inhibitors; D014468:Umbelliferones; D000255:Adenosine Triphosphate; D019859:Proto-Oncogene Proteins c-met; C039952:daphnetin