Abstract：
The colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum in vitro antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues C1∼J2 bearing diverse substituents and scaffolds. Among them, analogue G13 bearing a hydroxymethyl group displayed good tubulin polymerisation inhibitory activity (IC50 = 13.5 μM) and potent antiproliferative activity (IC50 values: 0.65 μM∼0.90 μM). G13 potently inhibited the migration and invasion of MDA-MB-231 cells, and displayed potent antiangiogenic activity. It efficiently increased intracellular ROS level and decreased MMP in cancer cells, and obviously induced the fragmentation and disassembly of the microtubules network. More importantly, G13 exhibited good in vivo antitumour efficacy in MDA-MB-231 xenograft model (TGI = 38.2%; i.p., 30 mg/kg).
摘要：
微管蛋白的秋水仙碱结合位点是发现新型抗肿瘤剂的有希望的靶标。以前,我们确定2-芳基-4-酰胺-喹啉衍生物显示中等微管蛋白聚合抑制活性和广谱体外抗肿瘤活性。在这项研究中,进行了基于结构的合理设计和系统的结构优化，以获得带有不同取代基和支架的类似物C1~J2。其中,带有羟甲基的类似物G13显示出良好的微管蛋白聚合抑制活性（IC50=13.5μM）和有效的抗增殖活性（IC50值：0.65μM〜0.90μM）。G13能有效抑制MDA-MB-231细胞的迁移和侵袭,并显示出有效的抗血管生成活性。它有效地增加细胞内ROS水平和减少癌细胞中的MMP，并明显诱导了微管网络的破碎和分解。更重要的是,G13在MDA-MB-231异种移植模型中表现出良好的体内抗肿瘤功效（TGI=38.2％；i.p.，30mg/kg)。
