New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis
| Autor: | Abdulrahman A. Almehizia, Mohammed A. Dahab, Ahmad J. Obaidullah, Hazem A. Mahdy, Nawaf A. Alsaif, Hazem Elkady, Saleh Aldawas, Manal M. Alanazi, Mohammed M. Alanazi |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Cell Survival Antineoplastic Agents Apoptosis 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Quinoxaline Cell Line Tumor Quinoxalines Drug Discovery Humans Cytotoxicity Protein Kinase Inhibitors Molecular Biology IC50 Caspase Cell Proliferation Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Kinase Organic Chemistry Vascular Endothelial Growth Factor Receptor-2 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Docking (molecular) Cell culture Drug Design biology.protein Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic Chemistry. 110:104807 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2021.104807 |
| Popis: | New series of [1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized, and biologically assessed for their anti-proliferative activities against two selected tumor cell lines MCF-7 and HepG2. Comparing to sorafenib (IC50 = 2.17 ± 0.13 and 3.51 ± 0.21 µM against MCF-7 and HepG2, respectively), compound 25d, 25e, 25i, and 27e exhibited the highest activities against the examined cell lines with IC50 values extending from 4.1 ± 0.4 to 11.7 ± 1.1 µM. Furthermore, VEGFR-2 inhibitory activities were assessed for all the synthesized compounds as potential mechanisms for their anti-proliferative activities. Compounds 25d, 25e, 25i, and 27e displayed prominent inhibitory efficiency versus VEGFR-2 kinase with IC50 value ranging from 3.4 ± 0.3 to 6.8 ± 0.5 nM. Fascinatingly, the results of VEGFR-2 inhibitory assays were matched with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited promising VEGFR-2 inhibitory activities. Further studies displayed the ability of compound 25d to induce apoptosis in HepG2 cells and can arrest the growth of such cells at the G2/M phase. Also, compound 25d produced a significant increase in the level of BAX/Bcl-2 ratio (3.8-fold), caspase- 3 (1.8-fold), and caspase-9 (1.9-fold) compared to the control cells. Molecular docking studies were carried out to investigate the possible binding interaction inside the active site of the VEGFR-2. |
| Databáze: | OpenAIRE |
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