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).

摘要

迫切需要设计新的抗癌剂，即使副作用最小，也可以防止癌细胞增殖。因此，设计了两个新系列的 3-methylquinoxalin-2( 1H )-one 和 3-methylquinoxaline-2-thiol 衍生物作为 VEGFR-2 抑制剂。设计的衍生物被合成并在体外评估为针对两种人类癌细胞系，即 HepG-2 和 MCF-7 的细胞毒性剂。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，以通过细胞周期和细胞凋亡分析获得有关其凋亡效应的宝贵见解。此外，对化合物11e进行了深入研究使用西方绘图分析检测其对一些凋亡和凋亡参数的影响，包括 caspase-9、caspase-3、BAX 和 Bcl-2。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（分别针对 MCF-7 和 HepG2 的IC ₅₀ = 3.4 和 2.2 µM ）相比，化合物11e、11g、12e、12g和12k表现出有希望的细胞毒活性（IC ₅₀范围为 2.1 - 9.8 µM ） . 此外，11b、11f、11g、12e、12f、12g和12k显示出最高的VEGFR-2抑制活性（IC₅₀范围为 2.9 − 5.4 µM)，与索拉非尼 (IC ₅₀ = 3.07 nM) 相比。此外，与对照细胞 (9.71%) 相比，化合物11e具有在 G2/M 期阻止 HepG2 细胞生长并诱导细胞凋亡 49.14% 的良好潜力。同样，这种化合物显示出 caspase-3（2.34 倍）、caspase-9（2.34 倍）和 BAX（3.14 倍）水平的显着增加，以及 Bcl-2 水平（3.13 -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。