3-methoxy-11-propyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 英文名称: 3-methoxy-11-propyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene
• 英文别名: (1S,9S,10S)-4-methoxy-17-propyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene
• 化学式: C₂₀H₂₉NO
• 分子量: 299.456
• InChiKey: LLKIPRRLVYWEHN-HOJAQTOUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  右美沙芬 在 potassium phosphate 、 potassium thioacetate 作用下， 以 环丁砜 为溶剂， 反应 11.0h， 生成 3-methoxy-11-propyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene
  参考文献：
  名称：

  Simple and selective one-pot replacement of the N-methyl group of tertiary amines by quaternization and demethylation with sodium sulfide or potassium thioacetate: an application to the synthesis of pergolide

  摘要：

  该论文描述了一种温和、选择性且迅速的三级胺N-甲基被其他烷基替换的方法，通过简单的单锅法实现。这一转变通过在环丁砜中制备适当的季铵盐，并现场用硫化钠或硫代乙酸钾处理即可轻松实现。该方案成功应用于将二氢麦角胺、右美沙芬和劳丹诺新（作为麦角和鸦片N-甲基生物碱的模型）转化为各种N-烷基类似物。

  DOI：

  10.1039/b104843k

文献信息

• Simple and selective one-pot replacement of the N-methyl group of tertiary amines by quaternization and demethylation with sodium sulfide or potassium thioacetate: an application to the synthesis of pergolide
  作者：Luigi Anastasia、Giuliana Cighetti、Pietro Allevi

  DOI：10.1039/b104843k

  日期：——

  The paper describes a mild, selective, and rapid replacement of an N-methyl group of tertiary amines with other alkyl groups via a simple one-pot procedure. This transformation is easily achieved by preparation of the appropriate quaternary ammonium salt in sulfolane and in situ treatment with sodium sulfide or potassium thioacetate. The protocol is successfully applied to the transformation of dihydrolysergol, dextromethorphan and laudanosine (as models of ergot and opium N-methyl alkaloids) into various N-alkyl congeners.

  该论文描述了一种温和、选择性且迅速的三级胺N-甲基被其他烷基替换的方法，通过简单的单锅法实现。这一转变通过在环丁砜中制备适当的季铵盐，并现场用硫化钠或硫代乙酸钾处理即可轻松实现。该方案成功应用于将二氢麦角胺、右美沙芬和劳丹诺新（作为麦角和鸦片N-甲基生物碱的模型）转化为各种N-烷基类似物。
• Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C–H Functionalization of Trialkylamine <i>N</i>-CH₃ Groups
  作者：Joshua P. Barham、Matthew P. John、John A. Murphy

  DOI：10.1021/jacs.6b09690

  日期：2016.11.30

  high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+•, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C-H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity

  我们报告了一个简单的一锅法，它提供了 N-甲基-N,N-二烷基胺中 N-CH3 基团的功能化，对 N-CH2R 或 N-CHR2 基团具有高选择性。通过用三芳基胺盐氧化 DABCO 原位制备的自由基阳离子 DABCO+• 从 N-CH3 基团中影响高选择性和逆热力学 CH 提取。产生的中间体在一个锅中与有机金属亲核试剂原位反应，提供新的和高度选择性的 N-CH3 基团同系化。证明了试剂的化学选择性、可扩展性和可回收性，并通过计算和实验结果证实了机制建议。转化的效用在天然产物和药物的后期位点选择性功能化中得到证明，
• Potent Antiplasmodial Derivatives of Dextromethorphan Reveal the Ent-Morphinan Pharmacophore of Tazopsine-Type Alkaloids
  作者：Antoinette Keita、Jean-François Franetich、Maëlle Carraz、Loïse Valentin、Mallaury Bordessoules、Ludivine Baron、Pierre Bigeard、Florian Dupuy、Valentine Geay、Maurel Tefit、Véronique Sarrasin、Sylvie Michel、Catherine Lavazec、Sandrine Houzé、Dominique Mazier、Valérie Soulard、François-Hugues Porée、Romain Duval

  DOI：10.3390/pharmaceutics14020372

  日期：——

  The alkaloid tazopsine 1 was introduced in the late 2000s as a novel antiplasmodial hit compound active against Plasmodium falciparum hepatic stages, with the potential to develop prophylactic drugs based on this novel chemical scaffold. However, the structural determinants of tazopsine 1 bioactivity, together with the exact definition of the pharmacophore, remained elusive, impeding further development. We found that the antitussive drug dextromethorphan (DXM) 3, although lacking the complex pattern of stereospecific functionalization of the natural hit, was harboring significant antiplasmodial activity in vitro despite suboptimal prophylactic activity in a murine model of malaria, precluding its direct repurposing against the disease. The targeted N-alkylation of nor-DXM 15 produced a small library of analogues with greatly improved activity over DXM 3 against P. falciparum asexual stages. Amongst these, N-2′-pyrrolylmethyl-nor-DXM 16i showed a 2- to 36-fold superior inhibitory potency compared to tazopsine 1 and DXM 3 against P. falciparum liver and blood stages, with respectively 760 ± 130 nM and 2.1 ± 0.4 μM IC50 values, as well as liver/blood phase selectivity of 2.8. Furthermore, cpd. 16i showed a 5- to 8-fold increase in activity relative to DXM 3 against P. falciparum stages I–II and V gametocytes, with 18.5 μM and 13.2 μM IC50 values, respectively. Cpd. 16i can thus be considered a promising novel hit compound against malaria in the ent-morphinan series with putative pan cycle activity, paving the way for further therapeutic development (e.g., investigation of its prophylactic activity in vivo).

  碱性物质tazopsine 1在2000年代后期作为一种新型抗疟疾活性化合物被引入，对恶性疟原虫肝阶段具有活性，并有潜力基于这种新型化学支架开发预防药物。然而，tazopsine 1的生物活性的结构决定因素，以及药效团的确切定义仍然难以捉摸，阻碍了进一步的发展。我们发现，虽然抗咳药物右美沙芬（DXM）3缺乏天然活性化合物的复杂立体特异性功能化模式，但在体外具有显著的抗疟疾活性，尽管在小鼠疟疾模型中的预防活性不佳，因此无法直接重新用于治疗疾病。对nor-DXM 15进行有针对性的N-烷基化产生了一个小型类似物库，这些类似物相对于DXM 3在恶性疟原虫无性阶段具有大幅改善的活性。在这些类似物中，N-2'-吡咯甲基- nor-DXM 16i对恶性疟原虫肝和血液阶段的抑制效力比tazopsine 1和DXM 3分别高出2至36倍，其IC50值分别为760 ± 130 nM和2.1 ± 0.4 μM，以及肝/血液阶段选择性为2.8。此外，化合物16i相对于DXM 3在恶性疟原虫I-II和V配子体阶段的活性增加了5至8倍，其IC50值分别为18.5 μM和13.2 μM。 因此，化合物16i可以被认为是一种有前景的新型抗疟疾活性化合物，在ent-吗啡类系列中具有潜在的全周期活性，为进一步的治疗开发铺平了道路（例如，对其在体内的预防活性进行研究）。