Abstract

Tubulin polymerisation inhibitors that target colchicine binding site were powerful anticancer agents. Although along the years many colchicine binding site inhibitors (CBSIs) have been reported, few piperidine derivatives were identified as CBSIs. In this regard, we focussed efforts on the piperidine as a promising chemotype to develop potent CBSIs. Herein, novel piperidine derivatives were synthesised and evaluated for their antiproliferative activities. Among them, compound 17a displayed powerful anticancer activity with the IC₅₀ value of 0.81 µM against PC3 cells, which was significantly better than 5-fluorouracil. It could inhibit tubulin polymerisation binding at the colchicine site and inhibit the tumour growth in vitro and in vivo. Further biological studies depicted that 17a suppressed the colony formation, induced apoptosis, and inhibited epithelial-mesenchymal transition against PC3 cells. These results revealed that compound 17a is a promising colchicine binding site inhibitor for the treatment of cancer and it is worthy of further exploitation.

摘要

靶向秋水仙碱结合位点的微管蛋白聚合抑制剂是强大的抗癌药。尽管多年来已经报道了许多秋水仙碱结合位点抑制剂（CBSI），但很少有人鉴定哌啶衍生物为CBSI。在这方面，我们将精力集中在哌啶上，作为开发有效CBSI的有前途的化学型。在此，合成了新的哌啶衍生物并评估了它们的抗增殖活性。其中，化合物17a对PC3细胞表现出强大的抗癌活性，IC ₅₀值为0.81 µM，明显优于5-氟尿嘧啶。它可以抑制微管蛋白聚合在秋水仙素位点结合并且抑制肿瘤生长的体外和体内。进一步的生物学研究表明17a抑制了针对PC3细胞的集落形成，诱导了细胞凋亡并抑制了上皮-间质转化。这些结果表明，化合物17a是一种有前途的秋水仙碱结合位点抑制剂，可用于治疗癌症，值得进一步开发。