药学学报, 2019, 54(3): 469-474
引用本文:
郑艳波, 弓建华, 许先栋, 甄永苏. 新型微管抑制剂IMB5046的合成及抗血管生成活性[J]. 药学学报, 2019, 54(3): 469-474.
ZHENG Yan-bo, GONG Jian-hua, XU Xian-dong, ZHEN Yong-su. Synthesis and anti-angiogenic activity of a novel microtubule inhibitor IMB5046[J]. Acta Pharmaceutica Sinica, 2019, 54(3): 469-474.

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:   
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 to examine the effect of IMB5046 on cell cycle. Cell wound scratch assay and Transwell assay were performed to examine cell migration. Endothelial tube formation assay was used to evaluate the anti-angiogenic activity of IMB5046. The results indicated that IMB5046 induced endothelial cell contraction and microtubule depolymerization, and inhibited the proliferation of endothelial cells and tumor cells, while two raw materials showed no obvious effects. IMB5046 arrested cell cycle at G2/M phase, even at low-cytotoxic concentrations it significantly inhibited the motility of endothelial cells. IMB5046 inhibited the tube formation of endothelial cells according to the number of tubes and junctions. In conclusion, IMB5046 is a promising microtubule-targeting drug with anti-angiogenic activity.
Key words:   
收稿日期: 2018-12-04
DOI: 10.16438/j.0513-4870.2018-1083
基金项目: 中国医学科学院医学与健康科技创新工程(2016-I2M-2-002,2017-I2M-1-010).
通讯作者: 甄永苏
Email: zhenys@imb.pumc.edu.cn
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