Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 36; no. 1; pp. 1732 - 1750
• Main Authors: Alanazi, Mohammed M., Elwan, Alaa, Alsaif, Nawaf A., Obaidullah, Ahmad J., Alkahtani, Hamad M., Al-Mehizia, Abdulrahman A., Alsubaie, Sultan M., Taghour, Mohammed S., Eissa, Ibrahim H.
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2021; Taylor & Francis Group
• Subjects: 3-methylquinoxalin-2(1H)-one; 3-methylquinoxaline-2-thiol; Animals; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; Biochemistry & Molecular Biology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Computer Simulation; Drug Discovery; Drug Screening Assays, Antitumor; Humans; in silico studies; Life Sciences & Biomedicine; Molecular Docking Simulation; Pharmacology & Pharmacy; Quinoxalines - chemical synthesis; Quinoxalines - pharmacokinetics; Quinoxalines - pharmacology; Rats; Research Paper; Science & Technology; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR-2 inhibitors; RAPID COLORIMETRIC ASSAY; VEGFR-2 inhibitors; QUINOXALINE DERIVATIVES; apoptosis; KINASE INHIBITORS; 3-methylquinoxaline-2-thiol; ANTI-HYPERGLYCEMIC EVALUATION; CLINICAL-TRIALS; BIOLOGICAL EVALUATION; 3-methylquinoxalin-2(1H)-one; GROWTH-FACTOR RECEPTOR-2; PPAR-GAMMA; CELL-CYCLE; Anticancer; in silico studies; RATIONAL DESIGN
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.1945591

There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC 50 range is 2.1 − 9.8 µM), comparing to sorafenib (IC 50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC 50 range is 2.9 − 5.4 µM), comparing to sorafenib (IC 50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).