3-benzyl-5-methoxychromen-2-one

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 3-benzyl-5-methoxychromen-2-one
• 英文别名: 3-benzyl-5-methoxy-2H-chromen-2-one；3-benzyl-5-methoxy-2H-1-benzopyran-2-one
• 化学式: C₁₇H₁₄O₃
• 分子量: 266.296
• InChiKey: XJSXZFXFKVCTQS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-benzyl-5-methoxychromen-2-one 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 24.5h， 以82%的产率得到3-benzyl-5-hydroxy-2H-chromen-2-one
  参考文献：
  名称：

  Synthesis, biochemical evaluation, and molecular modeling of organophosphate-coumarin hybrids as potent and selective butyrylcholinesterase inhibitors

  摘要：

  A small library of new organophosphorylated warfarins and 3-benzylcoumarins were synthesized and evaluated for in vitro cholinesterase inhibition by Ellman's method. Most of the compounds were found to be selective for butyrylcholinesterase (BChE) over acetylcholinesterase (AChE), with IC50 values ranging from 0.363 mu M to 53.0 mu M determined after 15 s of enzyme exposure. Comparison of the most potent compound, 3b with its constitutional isomer 2b revealed the high importance of phosphate positioning. Reversed selectivity and a 100-fold reduction in anti-BChE activity was observed when the organophosphate was attached to the benzyl instead of the coumarin. Docking calculations suggest that 3b binds initially as a transition state mimic with nearoptimal phosphate orientation relative to S198 and occupation of the oxyanion hole prior to phosphorylation. These results might inspire the design of a new type of non-neuropathic and irreversible coumarin-based inhibitor against BChE.

  DOI：

  10.1016/j.bmcl.2020.127213
• 作为产物：
  描述：

  反式肉桂醛 、 2-羟基-6-甲氧基苯甲醛 在 potassium carbonate 作用下， 以 甲苯 为溶剂， 反应 0.5h， 以50%的产率得到3-benzyl-5-methoxychromen-2-one
  参考文献：
  名称：

  利用亲核卡宾从水杨醛和 α,β-不饱和醛合成 3-烷基香豆素：一种新的多米诺反应

  摘要：

  从水杨醛和α,β-不饱和醛开始，提出了一种在离子液体中合成香豆素的新方法。关键特征是生成 N-杂环卡宾 (NHC) 和 Umpolung 反应。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

  DOI：

  10.1002/ejoc.200600718

文献信息

• Synthesis of 3-Alkylcoumarins from Salicylaldehydes and α,β-Unsaturated Aldehydes Utilizing Nucleophilic Carbenes: A New Umpoled Domino Reaction
  作者：Jakob Toräng、Sylvia Vanderheiden、Martin Nieger、Stefan Bräse

  DOI：10.1002/ejoc.200600718

  日期：2007.2

  Starting from salicylaldehydes and α,β-unsaturated aldehydes, a new coumarin synthesis in ionic liquids is presented. The key feature is the generation of N-heterocyclic carbenes (NHC) and an Umpolung reaction. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

  从水杨醛和α,β-不饱和醛开始，提出了一种在离子液体中合成香豆素的新方法。关键特征是生成 N-杂环卡宾 (NHC) 和 Umpolung 反应。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
• Synthesis and pharmacological evaluation of coumarin derivatives as cannabinoid receptor antagonists and inverse agonists
  作者：Andrea Behrenswerth、Nicole Volz、Jakob Toräng、Sonja Hinz、Stefan Bräse、Christa E. Müller

  DOI：10.1016/j.bmc.2009.02.027

  日期：2009.4

  In the present study we synthesized 36 coumarin and 2H-chromene derivatives applying a recently developed umpoled domino reaction using substituted salicylaldehyde and α,β-unsaturated aldehyde derivatives as starting compounds. In radioligand binding studies 5-substituted 3-benzylcoumarin derivatives showed affinity to cannabinoid CB1 and CB2 receptors and were identified as new lead structures. In

  在本研究中，我们使用取代的水杨醛和α，β-不饱和醛衍生物作为起始化合物，利用最近开发的本体化多米诺反应合成了36种香豆素和2 H-色烯衍生物。在放射性配体结合研究中，5取代的3-苄香豆素衍生物显示出对大麻素CB 1和CB 2受体的亲和力，并被确定为新的前导结构。在进一步的GTPγS结合研究中，选定的化合物显示为拮抗剂或反向激动剂。
• Antagonists for the Orphan G-Protein-Coupled Receptor GPR55 Based on a Coumarin Scaffold
  作者：Viktor Rempel、Nicole Volz、Franziska Gläser、Martin Nieger、Stefan Bräse、Christa E. Müller

  DOI：10.1021/jm4005175

  日期：2013.6.13

  The orphan G-protein-coupled receptor GPR55, which is activated by 1-lysophosphatidylinositol and interacts with cannabinoid (CB) receptor ligands, has been proposed as a new potential drug target for the treatment of diabetes, Parkinson's disease, neuropathic pain, and cancer. We applied beta-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists and performed an extensive structure-activity relationship study for GPR55. Selectivity versus the related receptors CB1, CB2, and GPR18 was assessed. Among the 7-unsubstituted coumarins selective, competitive GPR55 antagonists were identified, such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2H-chromen-2-one (12, PSB-SB-489, IC50 = 1.77 mu M, pA(2) = 0.547 mu M). Derivatives with long alkyl chains in position 7 were potent, possibly allosteric GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (69, PSB-SB-487, IC50 = 0.113 mu M, K-B = 0.561 mu M) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (67, PSB-SB-1203, IC50 = 0.261 mu M) were the most potent GPR55 antagonists of the present series.
• Synthesis, biochemical evaluation, and molecular modeling of organophosphate-coumarin hybrids as potent and selective butyrylcholinesterase inhibitors
  作者：Lee J. Macklin、Jason P. Schwans

  DOI：10.1016/j.bmcl.2020.127213

  日期：2020.7

  A small library of new organophosphorylated warfarins and 3-benzylcoumarins were synthesized and evaluated for in vitro cholinesterase inhibition by Ellman's method. Most of the compounds were found to be selective for butyrylcholinesterase (BChE) over acetylcholinesterase (AChE), with IC50 values ranging from 0.363 mu M to 53.0 mu M determined after 15 s of enzyme exposure. Comparison of the most potent compound, 3b with its constitutional isomer 2b revealed the high importance of phosphate positioning. Reversed selectivity and a 100-fold reduction in anti-BChE activity was observed when the organophosphate was attached to the benzyl instead of the coumarin. Docking calculations suggest that 3b binds initially as a transition state mimic with nearoptimal phosphate orientation relative to S198 and occupation of the oxyanion hole prior to phosphorylation. These results might inspire the design of a new type of non-neuropathic and irreversible coumarin-based inhibitor against BChE.