School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
Eur J Med Chem. 2021 Mar 5;213:113192. doi: 10.1016/j.ejmech.2021.113192. Epub 2021 Jan 18.
Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC = 0.36 ± 0.11 μM, as well as less toxicity against normal GES-1 cells with IC = 187.46 ± 10.13 μM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.
血管内皮生长因子-2（VEGFR-2）在肿瘤血管生成中起着关键作用。在此基础上，基于构效关系设计并合成了一系列新型的 2-(4-(1H-吲唑-6-基)-1H-吡唑-1-基)乙酰胺衍生物，作为 VEGFR-2 抑制剂。这些化合物对 VEGFR-2 和肿瘤细胞增殖均表现出良好的抑制作用。特别是化合物 W13 对 VEGFR-2 具有很强的抑制作用，IC 50 = 1.6 nM，对 HGC-27 肿瘤细胞的增殖抑制作用的 IC 50 = 0.36 ± 0.11 μM，对正常 GES-1 细胞的毒性较小，IC 50 = 187.46 ± 10.13 μM。此外，W13 通过调节 MMP-9 和 E-钙黏蛋白的表达，明显抑制 HGC-27 细胞的集落形成、迁移和侵袭，并通过增加 ROS 产生和调节凋亡蛋白的表达诱导 HGC-27 细胞凋亡。此外，W13 还能抑制 HGC-27 细胞中 PI3K-Akt-mTOR 信号通路。此外，W13 还通过抑制 HUVEC 细胞的管形成和 p-VEGFR-2 的表达来抑制血管生成。所有结果表明，W13 可能成为治疗胃癌的一种有前途的抗癌药物。
