N-nornuciferine | 4846-19-9

• 物质功能分类: 天然产物 - 生物碱
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 阿朴菲
• 英文名称: N-nornuciferine
• 英文别名: nornuciferine；(R)-nornuciferine；(6aR)-1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline
• CAS: 4846-19-9
• 化学式: C₁₈H₁₉NO₂
• 分子量: 281.354
• InChiKey: QQKAHDMMPBQDAC-CQSZACIVSA-N

物化性质

• 熔点：
  128-129℃
• 沸点：
  446.4±45.0 °C(Predicted)
• 密度：
  1.163±0.06 g/cm3 (20 ºC 760 Torr)
• 溶解度：
  可溶于DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  30.5
• 氢给体数：
  1
• 氢受体数：
  3

制备方法与用途

生物活性 N-Nornuciferine 是荷叶中的一种阿朴酚生物碱，显著抑制 CYP2D6 活性，其 IC50 和 Ki 值分别为 3.76 μM 和 2.34 μM。

靶点

• IC50: 3.76 μM (CYP2D6)
• Ki: 2.34 μM (CYP2D6)

体外研究 荷叶是传统中药的一种，具有广泛的药理和生理活性，特别是降低血液中的甘油三酯和胆固醇水平。N-Nornuciferine 强烈抑制 CYP2D6 活性，但对其他四种 P450 同工酶（CYP2C19、CYP3A4、CYP2E1 和 CYP2C9）的抑制作用较弱或无。N-Nornuciferine 竞争性地抑制 CYP2D6 催化的右美沙芬羟甲基化反应，其 K_i 值为 2.34 μM。

化学性质 N-Nornuciferine 是一种白色结晶粉末，可溶于甲醇、乙醇和 DMSO 等有机溶剂，来源于荷叶。

反应信息

• 作为反应物：
  描述：

  N-nornuciferine 在 sodium tetrahydroborate 、 二苄基二硒醚 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以73%的产率得到(-)-鹅掌楸宁碱
  参考文献：
  名称：

  Synthesis and structure–activity relationship of nuciferine derivatives as potential acetylcholinesterase inhibitors

  摘要：

  Acetylcholinesterase inhibitors (AChEIs) are currently the best available pharmacotherapy for Alzheimer patients, but because of bioavailability issues, there is still great interest in discovering better AChEIs. The aporphine alkaloid is an important class of natural products, which shows diverse biological activity, such as acetylcholinesterase inhibitory activity. To find new lead AChEIs compounds, eight aporphine alkaloids were synthesized by O-dealkylation, N-dealkylation, and ring aromatization reactions using nuciferine as raw material. The anti-acetylcholinesterase activity of synthesized compounds was measured using modified Ellman's method. The results showed that some synthesized compounds exhibited higher affinity to AChE than the parent compound nuciferine. Among these compounds, 1,2-dihydroxyaporphine (2) and dehydronuciferine (5) were the most active compounds (IC50 = 28 and 25 mu g/mL, respectively). Preliminary analysis of structure-activity relationships suggested that aromatization of the C ring, the presence of the alkoxyl group at C1 and the hydroxy group at C2 position as well as the alkyl substituent at the N atom were favorable to the acetylcholinesterase inhibition. Molecular docking was also applied to predict the binding modes of compounds 1, 2, and 9 into the huperzine A binding site of AChE.

  DOI：

  10.1007/s00044-013-0905-9
• 作为产物：
  描述：

  N-(3,4-二甲氧基苯乙基)乙酰胺 在 三乙胺 、 cesium fluoride 、 sodium hydroxide 、 lithium hydroxide 、 三氯氧磷 作用下， 以 乙醇 、 二氯甲烷 、 水 、 甲苯 、 乙腈 为溶剂， 反应 27.17h， 生成 N-nornuciferine
  参考文献：
  名称：

  使用苯并炔化学的立体选择性全合成（S）-和（R）-核苷

  摘要：

  （S）-和（R）-核苷的总合成是通过涉及手性二氢异喹啉烯酰胺与CsF促进的2-（三甲基甲硅烷基）苯基三氟甲磺酸酯之间的非对映选择性反应的方法完成的，从而提供了可分离的非对映异构体混合物，从而提供了（S）-和（R）-核苷通过简单而有效的转化。

  DOI：

  10.1016/j.tet.2020.131461

文献信息

• Aporphine Alkaloid Synthesis and Diversification via Direct Arylation
  作者：Marc Lafrance、Nicole Blaquiere、Keith Fagnou

  DOI：10.1002/ejoc.200600674

  日期：2007.2

  aporphines by reaction with benzodioxole, pyridine N-oxide and pyrazine N-oxide. Successful application of direct arylation in these diversification reactions highlights its utility not only in convergent, but also in divergent synthesis. We also describe enantioselective syntheses of (R)-nornuciferine and (R)-nuciferine employing a catalytic asymmetric transfer hydrogenation in high yield and excellent enantiomeric

  钯催化的芳基氯化物、溴化物和碘化物的直接芳基化已被应用于通过与苯并二恶唑、吡啶 N-氧化物和吡嗪 N-氧化物反应制备新的阿朴啡类似物，包括 C2 取代的阿朴啡。直接芳基化在这些多样化反应中的成功应用突出了其不仅在收敛合成中而且在发散合成中的效用。我们还描述了 (R)-nornuciferine 和 (R)-nuciferine 的对映选择性合成，采用催化不对称转移氢化以高产率和优异的对映体过量。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
• Synthesis, Antiacetylcholinesterase Activity, and Molecular Dynamics Simulation of Aporphine–benzylpyridinium Conjugates
  作者：Nisachon Khunnawutmanotham、Pichjira Sooknual、Paratchata Batsomboon、Poonsakdi Ploypradith、Nitirat Chimnoi、Apinya Patigo、Patchreenart Saparpakorn、Supanna Techasakul

  DOI：10.1021/acsmedchemlett.3c00467

  日期：2024.1.11

  for their acetylcholinesterase (AChE) inhibitory activity. The conjugation of the N-benzylpyridinium group significantly enhanced the AChE inhibitory activity of the core aporphine. The halogen substituents on the benzyl group affected the activity of the conjugates. Both (S)- and (R)-enantiomers of three conjugates with low IC50 values were synthesized and evaluated for their activities. All (S)-enantiomers

  合成了一系列通过酰胺键与N-苄基吡啶部分缀合的阿朴啡，并评估了它们的乙酰胆碱酯酶 (AChE) 抑制活性。 N-苄基吡啶鎓基团的缀合显着增强了核心阿朴啡的AChE抑制活性。苄基上的卤素取代基影响缀合物的活性。合成了三种具有低IC 50值的缀合物的( S )-和( R )-对映体并评估了它们的活性。所有 ( S )-对映体均表现出比相应的 ( R )-对映体更高的活性。含 2-氯苄基吡啶鎓的 ( S )-对映体阿朴啡是本研究中最有效的抑制剂，IC 50值为 0.06 ± 0.003 μM。分子动力学模拟分析表明，两种对映体都能与AChE结合位点相互作用，而( S )-对映体的相互作用略强于( R )-对映体，这可能是因为它们的方向不同，分子对接证明了这一点。还合成了N-苄基吡啶鎓脱氢阿朴啡缀合物，但其活性低于相应的阿朴啡缀合物。
• SANTAMARIA, J.;OUCHABANE, R.;RIGAUDY, J., TETRAHEDRON LETT., 30,(1989) N2, C. 2927-2928
  作者：SANTAMARIA, J.、OUCHABANE, R.、RIGAUDY, J.

  DOI：——

  日期：——
• Stereoselective total synthesis of (S)- and (R)-nuciferine using benzyne chemistry
  作者：Givago P. Perecim、Victor M. Deflon、Gabriel R. Martins、Leandro M.C. Pinto、Gleison A. Casagrande、Diogo Oliveira-Silva、Cristiano Raminelli

  DOI：10.1016/j.tet.2020.131461

  日期：2020.9

  Total syntheses of (S)- and (R)-nuciferine were accomplished through approach involving diastereoselective reaction between a chiral dihydroisoquinoline enamide and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate promoted by CsF, affording a separable mixture of diastereoisomers, which provided (S)- and (R)-nuciferine via simple and efficient transformations.

  （S）-和（R）-核苷的总合成是通过涉及手性二氢异喹啉烯酰胺与CsF促进的2-（三甲基甲硅烷基）苯基三氟甲磺酸酯之间的非对映选择性反应的方法完成的，从而提供了可分离的非对映异构体混合物，从而提供了（S）-和（R）-核苷通过简单而有效的转化。
• Synthesis and structure–activity relationship of nuciferine derivatives as potential acetylcholinesterase inhibitors
  作者：Zhongduo Yang、Zhuwen Song、Weiwei Xue、Jie Sheng、Zongmei Shu、Yin Shi、Jibei Liang、Xiaojun Yao

  DOI：10.1007/s00044-013-0905-9

  日期：2014.6

  Acetylcholinesterase inhibitors (AChEIs) are currently the best available pharmacotherapy for Alzheimer patients, but because of bioavailability issues, there is still great interest in discovering better AChEIs. The aporphine alkaloid is an important class of natural products, which shows diverse biological activity, such as acetylcholinesterase inhibitory activity. To find new lead AChEIs compounds, eight aporphine alkaloids were synthesized by O-dealkylation, N-dealkylation, and ring aromatization reactions using nuciferine as raw material. The anti-acetylcholinesterase activity of synthesized compounds was measured using modified Ellman's method. The results showed that some synthesized compounds exhibited higher affinity to AChE than the parent compound nuciferine. Among these compounds, 1,2-dihydroxyaporphine (2) and dehydronuciferine (5) were the most active compounds (IC50 = 28 and 25 mu g/mL, respectively). Preliminary analysis of structure-activity relationships suggested that aromatization of the C ring, the presence of the alkoxyl group at C1 and the hydroxy group at C2 position as well as the alkyl substituent at the N atom were favorable to the acetylcholinesterase inhibition. Molecular docking was also applied to predict the binding modes of compounds 1, 2, and 9 into the huperzine A binding site of AChE.