Yuan Minghua, Su Jingtian, Zhang Yixin, Qin Jinling, Yang Hua, Duan Yongtao, Yao Yongfang, Sun Moran
School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
Bioorg Med Chem Lett. 2023 Mar 1;83:129166. doi: 10.1016/j.bmcl.2023.129166. Epub 2023 Jan 31.
Tubulin, a potential target for antitumor drug discovery, contains three main binding sites for clinical inhibitors: colchicine, vinblastine, and paclitaxel. CA-4 has been reported to be a classic tubulin inhibitor targeting the colchicine site. Herein, based on the structural modification of CA-4, 48 novel compounds were designed and synthesized by selecting structural fragments with various biological activities to replace the cis double bond of CA-4. Among these compounds, compound 8p was the most effective tubulin inhibitor (IC = 65 nM aganist HepG2 cells). Immunofluorescence experiment confirmed the anti-tumor effect of 8p by destroying the network structure of microtubules. Further studies showed that 8p induced tumor cell apoptosis, arrested cell cycle, inhibited tumor cell migration and invasion.
微管蛋白是抗肿瘤药物研发的一个潜在靶点，它含有临床抑制剂的三个主要结合位点：秋水仙碱、长春碱和紫杉醇。CA-4已被报道是一种靶向秋水仙碱位点的经典微管蛋白抑制剂。在此，基于CA-4的结构修饰，通过选择具有各种生物活性的结构片段取代CA-4的顺式双键，设计并合成了48种新型化合物。在这些化合物中，化合物8p是最有效的微管蛋白抑制剂（对HepG2细胞的IC = 65 nM）。免疫荧光实验通过破坏微管网络结构证实了8p的抗肿瘤作用。进一步研究表明，8p诱导肿瘤细胞凋亡，使细胞周期停滞，抑制肿瘤细胞迁移和侵袭。
