微管被认为是癌症治疗的一个有吸引力的靶点。我们设计并合成了基于米帕钦的新型微管蛋白秋水仙碱结合位点抑制剂。生物学评价显示化合物5h对骨肉瘤细胞U2OS和MG-63表现出显着的抗增殖活性。化合物5h也显着抑制微管蛋白聚合。进一步的研究表明，化合物5h不仅使U2OS细胞周期阻滞在G2/M期，而且以剂量依赖性方式诱导U2OS细胞凋亡。此外，化合物5h被证实可抑制HUVECs的细胞迁移和血管生成，诱导线粒体膜电位降低并促进ROS水平升高。此外，化合物5h对体内肿瘤生长表现出显着的作用，20 mg/kg剂量下TGI率高达84.94%，且无明显毒性。这些结果表明 5h 可能是治疗骨肉瘤的一种有吸引力的微管蛋白抑制剂。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Microtubules are recognized as an appealing target for cancer treatment. We designed and synthesized of novel tubulin colchicine binding site inhibitors based on millepachine. Biological evaluation revealed compound 5h exhibited significant antiproliferative activity against osteosarcoma cell U2OS and MG-63. And compound 5h also remarkably inhibited tubulin polymerization. Further investigations indicated compound 5h not only arrest U2OS cells cycle at the G2/M phases, but also induced U2OS cells apoptosis in dose-dependent manners. Moreover, compound 5h was verified to inhibit cell migration and angiogenesis of HUVECs, induce mitochondrial membrane potential decreased and promoted the elevation of ROS levels. Furthermore, compound 5h exhibited remarkable effects on tumor growth in vivo, and the TGI rate was up to 84.94 % at a dose of 20 mg/kg without obvious toxicity. These results indicated that 5h may be an appealing tubulin inhibitor for treatment of osteosarcoma.Copyright © 2024 Elsevier Inc. All rights reserved.