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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

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
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

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
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

  • 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。
  • [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
    基金项目:  国家自然科学基金项目(81673352)

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
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
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