Abstract

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).

 抽象的

迫切需要设计新的抗癌药物，即使副作用最小，也能阻止癌细胞增殖。因此，设计了两个新系列的3-甲基喹喔啉-2( 1H )-酮和3-甲基喹喔啉-2-硫醇衍生物作为VEGFR-2抑制剂。合成了设计的衍生物，并在体外评估其作为针对两种人类癌细胞系（即 HepG-2 和 MCF-7）的细胞毒剂。此外，还评估了合成衍生物的 VEGFR-2 抑制作用。对最有希望的成员11e进行了进一步研究，通过细胞周期和细胞凋亡分析获得了关于其细胞凋亡效应的有价值的见解。此外，利用western-plot分析对化合物11e进行了深入研究，以检测其对一些凋亡和凋亡参数（包括caspase-9、caspase-3、BAX和Bcl-2）的影响。进行了许多计算机研究，包括对接、ADMET、毒性研究，以预测合成化合物的结合亲和力、药代动力学、药物相似性和毒性。结果表明，与索拉非尼相比，化合物11e、11g、12e、12g和12k表现出良好的细胞毒活性（IC ₅₀范围为 2.1 – 9.8 µM）（针对 MCF-7 和 HepG2，IC ₅₀分别为 3.4 和 2.2 µM） 。此外，与索拉非尼 (IC ₅₀ = 3.07 nM) 相比， 11b、11f、11g、12e、12f、12g和12k显示出最高的 VEGFR-2 抑制活性（IC ₅₀范围为 2.9 – 5.4 µM）。此外，化合物11e具有良好的潜力，可将 HepG2 细胞生长抑制在 G2/M 期并诱导细胞凋亡 49。与对照细胞 (9.71%) 相比，减少了 14%。此外，这种化合物还显着增加了 caspase-3（2.34 倍）、caspase-9（2.34 倍）和 BAX（3.14 倍）的水平，并显着降低了 Bcl-2 水平（3.13 倍）。 -折叠）。对于计算机研究，合成的化合物显示出与参考化合物（索拉非尼）相似的结合模式。