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类查尔酮Nrf2激活剂的合成及ARE诱导活性

胡文渊, 陈婕, 姜正羽, 王亚楼, 尤启冬

胡文渊, 陈婕, 姜正羽, 王亚楼, 尤启冬. 类查尔酮Nrf2激活剂的合成及ARE诱导活性[J]. 中国药科大学学报, 2016, 47(6): 666-672. DOI: 10.11665/j.issn.1000-5048.20160606
引用本文: 胡文渊, 陈婕, 姜正羽, 王亚楼, 尤启冬. 类查尔酮Nrf2激活剂的合成及ARE诱导活性[J]. 中国药科大学学报, 2016, 47(6): 666-672. DOI: 10.11665/j.issn.1000-5048.20160606
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HU Wenyuan, CHEN Jie, JIANG Zhengyu, WANG Yalou, YOU Qidong. Synthesis and biological activity of chalcone derivatives as potent activators of Nrf2[J]. Journal of China Pharmaceutical University, 2016, 47(6): 666-672. DOI: 10.11665/j.issn.1000-5048.20160606
Citation: HU Wenyuan, CHEN Jie, JIANG Zhengyu, WANG Yalou, YOU Qidong. Synthesis and biological activity of chalcone derivatives as potent activators of Nrf2[J]. Journal of China Pharmaceutical University, 2016, 47(6): 666-672. DOI: 10.11665/j.issn.1000-5048.20160606
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类查尔酮Nrf2激活剂的合成及ARE诱导活性

  • 1.

    中国药科大学 江苏省药物分子设计与成药性优化重点实验室

  • 2.

    中国药科大学 药物化学教研室

  • 3.

    合肥市第八中学

Synthesis and biological activity of chalcone derivatives as potent activators of Nrf2

摘要

    摘要
  • 摘要: 对先导化合物 CPUY191001 结构进行改造，以期得到活性更好的ARE-Nrf2激活剂。通过羟醛缩合反应合成17个目标化合物，采用MTT法测试目标化合物的抗增殖活性，并利用荧光素酶报告基因实验考察目标化合物对ARE的诱导活性。MTT数据显示，该系列化合物几乎无细胞毒性(IC50>；50 μmol/L)，活性测试结果表明，大部分类查尔酮衍生物对ARE具有一定的诱导活性，其中化合物 2 ， 3 ， 10 活性较优，且具有浓度依赖性。化合物 2 ， 3 ， 10 在抗炎与肿瘤预防治疗药物的研究领域中具有一定的应用前景，值得进一步研究。
    Abstract: To obtain ARE-Nrf2 potent activators through modifying the structure of the lead compound CPUY191001 . 17 compounds were synthesized by aldol condensation, their cytotoxicity were tested using MTT assay, and ARE inductivity of these target compounds were analyzed by luciferase reporter gene assay. The biological evaluation results showed that most synthesized chalcone derivatives nearly had no cytotoxicity, and compounds 2 , 3 , 10 conducted better activity and in concentration-dependent manner. Compounds 2 , 3 , 10 are potential agents in the development of anti-inflammatory and chemoprevention, suggesting that compounds 2 , 3 , 10 are worth for further investigation.
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    • 参考文献(12)
  • [1] Ohnuma T,Nakayama S,Anan E,et al.Activation of the Nrf2/ARE pathway via S-alkylation of cysteine 151 in the chemopreventive agent-sensor Keap1 protein by falcarindiol,a conjugated diacetylene compound[J].Toxicol Appl Pharmacol,2010,244(1):27-36.
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    [4] Shay KP,Michels AJ,Li W,et al.Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response[J].Biochim Biophys Acta,2012,1823(6):1102-1109.
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    [6] Satoh T,McKercher SR,Lipton SA.Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs[J].Free Radic Biol Med,2013,65:645-657.
    [7] Reisman SA,Buckley DB,Tanaka Y,et al.CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes[J].Toxicol Appl Pharmacol,2009,236(1):109-114.
    [8] Copple IM.The Keap1-Nrf2 cell defense pathway — a promising therapeutic target[J]?Adv Pharmacol,2012,63:43-79.
    [9] Marcotte D,Zeng W,Hus JC,et al.Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism[J].Bioorg Med Chem,2013,21(14):4011-4019.
    [10] Rex M,Yuesheng Z,Paonessa JD,et al.Synthesis,biological evaluation,and structure-activity relationships of dithiolethiones as inducers of cytoprotective phase 2 enzymes[J].J Med Chem,2010,53(12):4761-4767.
    [11] Xi MY,Sun ZY,Sun HP,et al.Synthesis and bioevaluation of a series of α-pyrone derivatives as potent activators of Nrf2/ARE pathway(part I)[J].Eur J Med Chem,2013,66:364-371.
    [12] Zhang DD.Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway[J].Drug Metabolism Reviews,2006, 38(4):769-789.
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  • 刊出日期:  2016-12-24

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