用于癌症治疗的双靶标药物比药物组合具有更多优势。这里,我们通过分子杂交策略设计并合成了一系列新型VEGFR-2/微管蛋白双靶点抑制剂,并测试了所有合成化合物对微管蛋白和VEGFR-2的活性。其中,化合物19对微管蛋白和VEGFR-2具有很强的效力,IC50值为0.76±0.11μM和15.33±2.12nM,分别。此外,化合物19不仅对一系列人类癌细胞系具有显著的抗增殖作用,特别是MGC-803细胞(IC50=0.005±0.001μM),但也克服了紫杉醇耐药MGC-803细胞的耐药性,RI为1.8。进一步研究表明,化合物19可通过降低线粒体膜电位诱导肿瘤细胞凋亡,增加ROS的水平,促进G2/M期停滞的诱导,并以剂量依赖的方式抑制肿瘤细胞的迁移和侵袭。此外,化合物19还通过阻断VEGFR-2/PI3K/AKT途径并抑制小管形成而表现出有效的抗血管生成作用,入侵,和HUVEC的迁移。更重要的是,化合物19表现出良好的药代动力学特征,强大的体内抗肿瘤功效,和令人满意的安全概况。总的来说,化合物19可作为开发微管蛋白/VEGFR-2双靶点抑制剂的先导化合物。
Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 μM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 μM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.