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非核苷类NEDD8活化酶抑制剂的设计、合成与活性研究

罗川,  喻支梁,  张万年,  缪震元

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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]. 药学实践与服务, 2020, 38(1): 35-41. doi: 10.3969/j.issn.1006-0111.201901012
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]. 药学实践与服务, 2020, 38(1): 35-41. doi: 10.3969/j.issn.1006-0111.201901012
shu
LUO Chuan, YU Zhiliang, ZHANG Wannian, MIAO Zhenyuan. Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(1): 35-41. doi: 10.3969/j.issn.1006-0111.201901012
Citation: LUO Chuan, YU Zhiliang, ZHANG Wannian, MIAO Zhenyuan. Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(1): 35-41. doi: 10.3969/j.issn.1006-0111.201901012
shu

非核苷类NEDD8活化酶抑制剂的设计、合成与活性研究

doi: 10.3969/j.issn.1006-0111.201901012
  • 1.

    安徽华润金蟾药业股份有限公司, 安徽 淮北 235000

  • 2.

    海军军医大学药学院药物化学教研室, 上海 200433

基金项目: 国家自然科学基金项目（81673352）

Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors

  • 1.

    Anhui Huarun Golden Frog Pharmaceutical Co., Ltd., Huaibei 235000, China

  • 2.

    Department of Medicinal Chemistry, School of Pharmacy, Naval Medical University, Shanghai 200433, China

  • 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。
    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.
  • [1] SOUCY T A, SMITH P G, MILHOLLEN M A, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer[J]. Nature,2009,458(7239):732-736
    [2] SWORDS R T, KELLY K R, SMITH P G, et al. Inhibition of NEDD8-activating enzyme: A novel approach for the treatment of acute myeloid leukemia[J]. Blood,2010,115(18):3796-3800
    [3] TANAKA T, NAKATANI T, KAMITANI T. Inhibition of NEDD8-conjugation pathway by novel molecules: potential approaches to anticancer therapy[J]. Mol Oncol,2012,6(3):267-275
    [4] XU B, DENG Y Y, BI R, et al. A first-in-class inhibitor, MLN4924 (pevonedistat), induces cell-cycle arrest, senescence, and apoptosis in human renal cell carcinoma by suppressing UBE2M-dependent neddylation modification[J]. Cancer Chemother Pharmacol,2018,81(6):1083-1093
    [5] LU P, GUO Y H, ZHU L J, et al. A novel NAE/UAE dual inhibitor LP0040 blocks neddylation and ubiquitination leading to growth inhibition and apoptosis of cancer cells[J]. Eur J Med Chem,2018,154:294-304
    [6] ZHANG S P, TAN J N, LAI Z H, et al. Effective virtual screening strategy toward covalent ligands: identification of novel NEDD8-activating enzyme inhibitors[J]. J Chem Inf Model,2014,54(6):1785-1797
    [7] ZHONG H J, LEUNG K H, LIN S, et al. Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme[J]. Methods,2015,71:71-76
    [8] VERMA S, SINGH A, MISHRA A. Molecular dynamics investigation on the poor sensitivity of A171T mutant NEDD8-activating enzyme (NAE) for MLN4924[J]. J Biomol Struct Dyn,2014,32(7):1064-1073
    [9] MIAO Z Y, ZHU L J, DONG G Q, et al. A new strategy to improve the metabolic stability of lactone: discovery of (20S, 21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors[J]. J Med Chem,2013,56(20):7902-7910
    [10] WU K J, ZHONG H J, LI G D, et al. Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing[J]. Eur J Med Chem,2018,143:1021-1027
    [11] LEE H W, NAM S K, CHOI W J, et al. Stereoselective synthesis of MLN4924, an inhibitor of NEDD8-activating enzyme[J]. J Org Chem,2011,76(9):3557-3561
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  • 收稿日期:  2019-01-10
  • 修回日期:  2019-04-17

非核苷类NEDD8活化酶抑制剂的设计、合成与活性研究

doi: 10.3969/j.issn.1006-0111.201901012
  • 1. 安徽华润金蟾药业股份有限公司, 安徽 淮北 235000
  • 2. 海军军医大学药学院药物化学教研室, 上海 200433
    • 基金项目:  国家自然科学基金项目（81673352）
  • 收稿日期: 2019-01-10
  • 修回日期: 2019-04-17

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。

English Abstract

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]. 药学实践与服务, 2020, 38(1): 35-41. doi: 10.3969/j.issn.1006-0111.201901012
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]. 药学实践与服务, 2020, 38(1): 35-41. doi: 10.3969/j.issn.1006-0111.201901012
shu
LUO Chuan, YU Zhiliang, ZHANG Wannian, MIAO Zhenyuan. Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(1): 35-41. doi: 10.3969/j.issn.1006-0111.201901012
Citation: LUO Chuan, YU Zhiliang, ZHANG Wannian, MIAO Zhenyuan. Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(1): 35-41. doi: 10.3969/j.issn.1006-0111.201901012
shu

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