Discovery of 8-Amino-Substituted 2-Phenyl-2,7-Naphthyridinone Derivatives as New c-Kit/VEGFR-2 Kinase Inhibitors
| Autor: | Wei Huang, Lin-Sheng Zhuo, She Nengfang, Haiyan Sun, Huan Dong |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
kinase inhibitor VEGF receptors Naphthyridinone Pharmaceutical Science 01 natural sciences Article Analytical Chemistry 03 medical and health sciences c-Kit Drug Discovery Ic50 values Humans Physical and Theoretical Chemistry IC50 Protein Kinase Inhibitors 030304 developmental biology 0303 health sciences biology 010405 organic chemistry Chemistry Kinase Organic Chemistry 2 7-naphthyridone Vascular Endothelial Growth Factor Receptor-2 0104 chemical sciences Molecular Docking Simulation Proto-Oncogene Proteins c-kit VEGFR-2 Chemistry (miscellaneous) Lead structure biology.protein Molecular Medicine |
| Zdroj: | Molecules Volume 24 Issue 24 |
| ISSN: | 1420-3049 |
| Popis: | The 2,7-naphthyridone scaffold has been proposed as a novel lead structure of MET inhibitors by our group. To broaden the application of this new scaffold, a series of 8-amino-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one derivatives were designed and synthesized. Preliminary biological screening resulted in the discovery of a new lead of c-Kit and VEGFR-2 kinase inhibitors. Compound 9k exhibited excellent c-Kit inhibitory activity, with an IC50 value of 8.5 nM, i.e., it is 38.8-fold more potent than compound 3 (IC50 of 329.6 nM). Moreover, the compounds 10l and 10r exhibited good VEGFR-2 inhibitory activity, with IC50 values of 56.5 and 31.7 nM, respectively, i.e., they are 5.0&ndash 8.8-fold more potent than compound 3 (IC50 of 279.9 nM). Molecular docking experiments provided further insight into the binding interactions of the new lead compounds with c-Kit and VEGFR-2 kinase. In this study, an 8-amino-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one scaffold was identified as the new lead structure of c-Kit and VEGFR-2 kinase inhibitors. |
| Databáze: | OpenAIRE |
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