Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 168, Issue -, Pages 315-329Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.02.050
Keywords
Picolinamide; Kinase inhibition; A549; VEGFR-2; Cell cycle analysis; Apoptosis; Binding DFG motif
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Funding
- Research Unit, Mansoura University, Egypt
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Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 91 showed potent inhibitory activity against VEGFR-2 kinase with IC50 values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC50 = 180 nM) as a reference. Compounds 7h, 9a and 91 were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining. (C) 2019 Elsevier Masson SAS. All rights reserved.
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