Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, 13713, Saudi Arabia.
Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):2191-2205. doi: 10.1080/14756366.2022.2110869.
New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds and showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound to prevent healing and migration abilities in the cancer cells. Furthermore, compound induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound in the active pocket of VEGFR-2 over 100 ns.
合成了具有 VEGFR-2 抑制剂主要特征的新喹啉和色酮衍生物。这些化合物的抗增殖作用在 A549、Caco-2、HepG2 和 MDA-MB-231 细胞系中进行了评估。化合物 和 对 Caco-2 细胞的活性与阿霉素相当。这些化合物强烈抑制 VEGFR-2 激酶活性。细胞毒性活性在 Vero 细胞中进行了评估。化合物 表现出最高的安全性和选择性。细胞迁移实验显示化合物 能够阻止癌细胞的愈合和迁移能力。此外，化合物 通过下调凋亡基因 Bcl2、Bcl-xl 和 Survivin 的表达以及上调 TGF 基因，诱导 Caco-2 细胞凋亡。针对 VEGFR-2 的分子对接表明，合成化合物的相互作用方式与索拉非尼相似。此外，还进行了七次分子动力学模拟研究，证实了化合物 在 VEGFR-2 的活性口袋中 100ns 以上的稳定性。
