新型微管抑制剂IMB5046的合成及抗血管生成活性-药学学报.PDFVIP

药学学报 Acta Pharmaceutica Sinica 2019, 54(3): 469 −474 ·469 · 新型微管抑制剂IMB5046 的合成及抗血管生成活性 郑艳波, 弓建华, 许先栋, 甄永苏* ( 中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050) 摘要: IMB5046 是新发现的硝基苯甲酸类微管抑制剂, 本文报道了IMB5046 的合成过程及其体外抗血管生成 活性。本研究以2-(4-吗啉基)-5-硝基苯甲酸与4- 甲硫基苄醇通过两步反应生成IMB5046, 终产物结构经1H NMR 和 HR-MS 确证。MTT 法检测化合物对细胞增殖的影响; 荧光法检测化合物对细胞骨架的影响; 流式细胞术检测 IMB5046 对细胞周期的影响; 划痕及Transwell 实验检测细胞的运动能力; 内皮小管形成实验检测IMB5046 对血管 生成的影响。结果显示IMB5046 可诱导血管内皮细胞的收缩及微管骨架的解聚, 抑制内皮细胞及肿瘤细胞的增 殖。两种原料药对细胞形态、微管结构及细胞生长均没有明显影响。IMB5046 将内皮细胞阻滞于G2/M 期。较低细 胞毒浓度的IMB5046 即可显著抑制内皮细胞的运动能力。IMB5046 可抑制内皮小管的形成, 使内皮小管数及节点 数显著减少。以上结果表明, IMB5046 有希望成为一种具有抗血管生成活性的靶向微管药物。 关键词: 微管抑制剂; IMB5046; 合成; 抗血管生成 中图分类号: R966 文献标识码: A 文章编号: 0513-4870(2019)03-0469-06 Synthesis and anti-angiogenic activity of a novel microtubule inhibitor IMB5046 ZHENG Yan-bo, GONG Jian-hua, XU Xian-dong, ZHEN Yong-su* (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China) Abstract: IMB5046 is a newly discovered nitrobenzoate functioning as a microtubule inhibitor. Here we report its synthesis and in vitro anti-angiogenic activity. IMB5046 was synthesized by conjugation of 2-morpholin- 4-yl-5-nitrobenzoic acid with 4-(methylthio)benzyl alcohol via two-step reactions. The structure of the end product was verified using 1H NMR and HR-MS spectroscopy. The effect of these compounds on cell proliferation was determined using MTT assay, and their impact on cytoskeleton was investigated using fluorescence assay. Flow cytometry was performed t