| Autor: |
Mohammed M. Alanazi, Ahmad J. Obaidullah, Nawaf A. Alsaif, Madhawi A. Alharbi, Manal M. Alanazi, Ibrahim H. Eissa, Hamad M. Alkahtani, Mohammed A. Dahab, Hazem Elkady |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
RSC Advances. 11:30315-30328 |
| ISSN: |
2046-2069 |
| DOI: |
10.1039/d1ra05925d |
| Popis: |
A new series of 3-methylquinoxaline-based derivatives having the same essential pharmacophoric features as VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against two human cancer cell lines, MCF-7 and HepG-2. Compounds 15b and 17b demonstrated a significant antiproliferative effect with IC50 ranging from 2.3 to 5.8 μM. An enzymatic assay was carried out for all the tested candidates against VEGFR-2. Compound 17b was the most potent VEGFR-2 inhibitor (IC50 = 2.7 nM). Mechanistic investigation including cell cycle arrest and apoptosis was performed for compound 17b against HepG-2 cells, and the results revealed that 17b induced cell apoptosis and arrested cell cycle in the G2/M phase. Moreover, apoptosis analyses were conducted for compound 17b to evaluate its apoptotic potential. The results showed upregulation in caspase-3 and caspase-9 levels, and improving the Bax/Bcl-2 ratio by more than 10-fold. Docking studies were performed to determine the possible interaction with the VEGFR-2 active site. Further docking studies were carried out for compound 17b against cytochrome P450 to present such compounds as non-inhibitors. In silico ADMET, toxicity, and physico-chemical properties revealed that most of the synthesized members have acceptable values of drug-likeness. Finally, DFT studies were carried out to calculate the thermodynamic, molecular orbital and electrostatic potential properties. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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