Abstract

Angiogenesis plays an important role in tumour generation and progression, which is used to supply nutrients and metastasis. Herein, a series of novel dihydro-1H-indene derivatives were designed and evaluated as tubulin polymerisation inhibitors by binding to colchicine site, exhibiting anti-angiogenic activities against new vessel forming. Through structure-activity relationships study, compound 12d was found to be the most potent derivative possessing the antiproliferative activity against four cancer lines with IC₅₀ values among 0.028−0.087 µM. Compound 12d bound to colchicine site on tubulin and inhibited tubulin polymerisation in vitro. In addition, compound 12d induced cell cycle arrest at G2/M phase, stimulated cell apoptosis, inhibited tumour metastasis and angiogenesis. Finally, the results of in vivo assay suggested that compound 12d could prevent tumour generation, inhibit tumour proliferation and angiogenesis without obvious toxicity. Collectively, all these findings suggested that compound 12d is a novel tubulin polymerisation inhibitor deserving further research.

摘要

血管生成在肿瘤的产生和进展中发挥着重要作用，用于供应营养和转移。在此，设计了一系列新型二氢-1H-茚衍生物，并通过与秋水仙碱位点结合作为微管蛋白聚合抑制剂进行评估，表现出针对新血管形成的抗血管生成活性。通过构效关系研究，发现化合物12d是对四种癌细胞系具有抗增殖活性的最有效的衍生物，IC ₅₀值在0.028−0.087  µM之间。化合物12d与微管蛋白上的秋水仙碱位点结合，并在体外抑制微管蛋白聚合。。此外，化合物12d诱导细胞周期停滞在G2/M期，刺激细胞凋亡，抑制肿瘤转移和血管生成。最后，体内实验结果表明，化合物12d可以阻止肿瘤生成、抑制肿瘤增殖和血管生成，且无明显毒性。总的来说，所有这些发现表明化合物12d是一种新型微管蛋白聚合抑制剂，值得进一步研究。