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

Journal of Enzyme Inhibition and Medicinal Chemistry

Abdulrahman A. Al-Mehizia¹  Ahmad J. Obaidullah¹  Nawaf A. Alsaif¹  Hamad M. Alkahtani¹  Sultan M. Alsubaie¹  Mohammed M. Alanazi¹  Ibrahim H. Eissa²  Mohammed S. Taghour²  Alaa Elwan² 

[1] Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabi;Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egyp;

关键词: Anticancer;    apoptosis;    in silico studies;    3-methylquinoxalin-2(1H)-one;    3-methylquinoxaline-2-thiol;    VEGFR-2 inhibitors;   

DOI  :  10.1080/14756366.2021.1945591

来源: Taylor & Francis

【 摘 要 】

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 (IC50 range is 2.1 − 9.8 µM), comparing to sorafenib (IC50 = 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 (IC50 range is 2.9 − 5.4 µM), comparing to sorafenib (IC50 = 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).

【 授权许可】

CC BY