非核苷类NAE抑制剂的设计、合成与活性研究
投稿时间:2019-01-10  修订日期:2019-04-17  点此下载全文
引用本文:
摘要点击次数: 265
全文下载次数: 0
作者单位E-mail
罗川 安徽华润金蟾药业股份有限公司 luoch51@126.com 
喻支梁 第二军医大学药学院药物化学教研室  
张万年 第二军医大学药学院药物化学教研室  
缪震元 第二军医大学药学院药物化学教研室  
基金项目:] 国家自然科学(项目编号:81373331)
中文摘要:目的 采用骨架跃迁策略设计非核苷类NAE抑制剂,并测试其抗肿瘤活性。方法 通过23步反应以较高收率合成出双磺酰胺类化合物14,通过1H NMR和MS确证其化学结构,采用MTT法测试体外抗肿瘤活性。结果化合物14对多种肿瘤细胞株显示出较好的活性,并呈剂量依赖性引起UBC12蛋白累积。 结论 化合物14是全新骨架的NAE抑制剂,在前列腺肿瘤细胞PANC-1中能显著引起细胞凋亡和细胞周期阻滞,为后续NAE抑制剂研究提供了一个有价值的先导化合物。
中文关键词:NAE,吲唑,骨架跃迁,抗肿瘤活性
 
Design, Synthesis and Biological Activity of Non-nucleoside NAE Inhibitors
Abstract:Objective To find novel NAE inhibitors with non-nucleoside scaffold by a scaffold hopping strategy and test their in vitro antitumor activities. Methods Disulfonamideindazole 14 was synthesized through a total route in 23 steps with a good yield, whose chemical structures were confirmed by 1H NMR and MS. MTT method was used to determine the in vitro antitumor activities. Results: Compound 14 exhibited moderate antitumor activities against all the cancer cells and promoted significant UBC12 accumulation in a dose-dependent manner consistent. Conclusion: Compound 14 is a potent NAE inhibitor with remarkable apoptosis induction and cell cycle arrest in prostate cancer PANC-1 cells. Our findings provide a new structural framework for further NAE inhibitor design.
keywords:NAE, indazole, scaffold  hopping, antitumor  activity
  查看/发表评论  下载PDF阅读器
相关附件:   万方20190110(13.89%)  万方20190314_审稿(12.92%)  万方20190417_审稿(17.88%)
关闭

分享按钮