Design, synthesis, in-vitro antiproliferative activity and kinase profile of new picolinamide based 2-amido and ureido quinoline derivatives

Title
Design, synthesis, in-vitro antiproliferative activity and kinase profile of new picolinamide based 2-amido and ureido quinoline derivatives
Authors
아쉬라프 카림서선희조남철강순방배애님김기선금교창
Keywords
Antiproliferative activity; Quinoline; Urea; Amide; Picolinamide; BRAFV600E; C-RAF
Issue Date
2015-08
Publisher
European journal of medicinal chemistry
Citation
VOL 101, 754-768
Abstract
New 2-amido and ureido quinoline derivatives substituted with 2-N-methylamido-pyridin-4-yloxy group at the 5-position of quinoline (18 final compounds) have been designed and synthesized as anticancer sorafenib congeners. Among the synthesized derivatives, fourteen compounds were selected for evaluation of their antiproliferative activity over a panel of 60 cancer cell lines at a single dose concentration of 10 mM at National Cancer Institute (NCI, USA). Four compounds, 9bed and 9f showed promising mean growth inhibitions and thus were further tested at five-dose testing mode to determine their IC50 values. The data revealed that 2,4-difluorophenyl (9b) and 4-chloro-3-trifluoromethylphenyl (9d) urea compounds are the most active derivatives with significant efficacies and superior potencies than sorafenib in 36 and 12 cancer cell lines, respectively, belonging particularly to renal carcinoma cell (RCC), ovarian, and non small cell lung cancer (NSCL). Compound 9b and 9d were found to be six and two times more potent than sorafenib against A498 RCC line, with IC50 values of 0.42 mM and 1.36 mM, respectively. Accordingly, compound 9d was screened over a panel of 41 oncogenic kinases at a single dose concentration of 10 mM to profile its kinase inhibitory activity. Interestingly, the compound showed highly selective inhibitory activities ( 81.8% and 96.3%) against BRAFV600E and C-RAF kinases with IC50 values of 316 nM and 61 nM, respectively. In addition, molecular docking, cell cycle analysis, compliance to Lipinski's rule of five, and in silico toxicity assessment have been reported.
URI
http://pubs.kist.re.kr/handle/201004/50417
ISSN
02235234
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KIST Publication > Article
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