| 非核苷类NEDD8活化酶抑制剂的设计、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：罗川,喻支梁,张万年,缪震元.非核苷类NEDD8活化酶抑制剂的设计、合成与活性研究[J].药学实践杂志,2020,38(1):35~41 |
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| 基金项目:国家自然科学基金项目（81673352） |
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| 中文摘要:目的 采用骨架跃迁策略设计非核苷类NEDD8活化酶（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:NEDD8活化酶 吲唑 骨架跃迁 抗肿瘤活性 体外 |
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| Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors |
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| Abstract:Objective To develop novel NAE inhibitors with non-nucleoside scaffold by a scaffold hopping strategy and study the in vitro antitumor activities.Methods Disulfonamideindazole 14 was synthesized through 23 steps with a good yield. Its chemical structure was 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 various cancer cells and promoted significant UBC12 accumulation in a dose-dependent manner.Conclusion Compound 14 is a potent NAE inhibitor with remarkable apoptosis induction and cell cycle arrest in prostate cancer PANC-1 cells. Our work provides a valuable leading compound for the further design and development of NAE inhibitors. |
| keywords:NAE indazole scaffold hopping antitumor activity in vitro |
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