(E)-5-(hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-3-[5-methyl-3-(2-methylpropyl)hexylidene]-4,5-dihydrofuran-2-one | 862549-24-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (E)-5-(hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-3-[5-methyl-3-(2-methylpropyl)hexylidene]-4,5-dihydrofuran-2-one
• 英文别名: 5-hydroxymethyl-3-[(E)-3-isobutyl-5-methylhexylidene]-5-[(4-methoxyphenoxy)methyl]tetrahydro-2-furanone；(3E)-5-(hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-3-[5-methyl-3-(2-methylpropyl)hexylidene]oxolan-2-one
• CAS: 862549-24-4
• 化学式: C₂₄H₃₆O₅
• 分子量: 404.547
• InChiKey: RTKHHQACAMJLPP-IFRROFPPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (E)-5-(hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-3-[5-methyl-3-(2-methylpropyl)hexylidene]-4,5-dihydrofuran-2-one 在 4-二甲氨基吡啶 、 ammonium cerium(IV) nitrate 、 三乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 3.67h， 生成 Benzoic acid 2-hydroxymethyl-4-[3-isobutyl-5-methyl-hex-(E)-ylidene]-5-oxo-tetrahydro-furan-2-ylmethyl ester
  参考文献：
  名称：

  Branched Diacylglycerol-Lactones as Potent Protein Kinase C Ligands and α-Secretase Activators

  摘要：

  Using as our lead structure a potent PKC ligand (1) that we had previously described, we investigated a series of branched DAG-lactones to optimize the scaffold for PKC binding affinity and reduced lipophilicity, and we examined the potential utility of select compounds as alpha-secretase activators. Activation of alpha-secretase upon PKC stimulation by ligands causes increased degradation of the amyloid precursor protein (APP), resulting in enhanced secretion of sAPP alpha and reduced deposition of beta-amyloid peptide (A beta), which is implicated in the pathogenesis of Alzheimer's disease. We modified in a systematic manner the C-5-acyl group, the 3-alkylidene, and the lactone ring in I and established structure-activity relationships for this series of potent PKC ligands. Select DAG-lactones with high binding affinities for PKC were evaluated for their abilities to lead to increased sAPP alpha secretion as a result of alpha-secretase activation. The DAG-lactones potently induced alpha-secretase activation, and their potencies correlated with the corresponding PKC binding affinities and lipophilicities. Further investigation indicated that 2 exhibited a modestly higher level of sAPP alpha secretion than did phorbol 12,13-dibutyrate (PDBu).

  DOI：

  10.1021/jm0509391
• 作为产物：
  描述：

  5-[(4-methoxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydrofuran-2-one 在 三氯化硼 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 (E)-5-(hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-3-[5-methyl-3-(2-methylpropyl)hexylidene]-4,5-dihydrofuran-2-one
  参考文献：
  名称：

  Design and synthesis of protein kinase C epsilon selective diacylglycerol lactones (DAG-lactones)

  摘要：

  DAG-lactones afford a synthetically accessible, high affinity platform for probing structure activity relationships at the Cl regulatory domain of protein kinase C (PKC). Given the central role of PKC isoforms in cellular signaling, along with their differential biological activities, a critical objective is the design of isoform selective ligands. Here, we report the synthesis of a series of DAG-lactones varying in their side chains, with a particular focus on linoleic acid derivatives. We evaluated their selectivity for PKC epsilon versus PKC alpha both under standard lipid conditions (100% phosphatidylserine, PS) as well as in the presence of a nuclear membrane mimetic lipid mixture (NML). We find that selectivity for PKC epsilon versus PKC alpha tended to be enhanced in the presence of the nuclear membrane mimetic lipid mixture and, for our lead compound, report a selectivity of 32-fold. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.11.025

文献信息

• Conformationally Constrained Analogues of Diacylglycerol (DAG). 25. Exploration of the <i>sn</i>-1 and <i>sn</i>-2 Carbonyl Functionality Reveals the Essential Role of the <i>sn</i>-1 Carbonyl at the Lipid Interface in the Binding of DAG-Lactones to Protein Kinase C
  作者：Ji-Hye Kang、Megan L. Peach、Yongmei Pu、Nancy E. Lewin、Marc C. Nicklaus、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm050352m

  日期：2005.9.1

  Diacylglycerol (DAG) lactones with altered functionality (C=O -> CH2 or C=O -> C=S) at the sn-1 and sn-2 carbonyl pharmacophores were synthesized and used as probes to dissect the individual role of each carbonyl in the binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen-bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (Cl domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-6 and Z-7, were designed to bind exclusively in the sn-2 binding mode to ensure the correct orientation and disposition of pharmacophores at the binding site.
• Design and synthesis of protein kinase C epsilon selective diacylglycerol lactones (DAG-lactones)
  作者：Jihyae Ann、Suyoung Yoon、Jisoo Baek、Da Hye Kim、Nancy E. Lewin、Colin S. Hill、Peter M. Blumberg、Jeewoo Lee

  DOI：10.1016/j.ejmech.2014.11.025

  日期：2015.1

  DAG-lactones afford a synthetically accessible, high affinity platform for probing structure activity relationships at the Cl regulatory domain of protein kinase C (PKC). Given the central role of PKC isoforms in cellular signaling, along with their differential biological activities, a critical objective is the design of isoform selective ligands. Here, we report the synthesis of a series of DAG-lactones varying in their side chains, with a particular focus on linoleic acid derivatives. We evaluated their selectivity for PKC epsilon versus PKC alpha both under standard lipid conditions (100% phosphatidylserine, PS) as well as in the presence of a nuclear membrane mimetic lipid mixture (NML). We find that selectivity for PKC epsilon versus PKC alpha tended to be enhanced in the presence of the nuclear membrane mimetic lipid mixture and, for our lead compound, report a selectivity of 32-fold. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Branched Diacylglycerol-Lactones as Potent Protein Kinase C Ligands and α-Secretase Activators
  作者：Jeewoo Lee、Ji-Hye Kang、Kee-Chung Han、Yerim Kim、Su Yeon Kim、Hae-Suk Youn、Inhee Mook-Jung、Hee Kim、Jee Hye Lo Han、Hee Jin Ha、Young Ho Kim、Victor E. Marquez、Nancy E. Lewin、Larry V. Pearce、Daniel J. Lundberg、Peter M. Blumberg

  DOI：10.1021/jm0509391

  日期：2006.3.1

  Using as our lead structure a potent PKC ligand (1) that we had previously described, we investigated a series of branched DAG-lactones to optimize the scaffold for PKC binding affinity and reduced lipophilicity, and we examined the potential utility of select compounds as alpha-secretase activators. Activation of alpha-secretase upon PKC stimulation by ligands causes increased degradation of the amyloid precursor protein (APP), resulting in enhanced secretion of sAPP alpha and reduced deposition of beta-amyloid peptide (A beta), which is implicated in the pathogenesis of Alzheimer's disease. We modified in a systematic manner the C-5-acyl group, the 3-alkylidene, and the lactone ring in I and established structure-activity relationships for this series of potent PKC ligands. Select DAG-lactones with high binding affinities for PKC were evaluated for their abilities to lead to increased sAPP alpha secretion as a result of alpha-secretase activation. The DAG-lactones potently induced alpha-secretase activation, and their potencies correlated with the corresponding PKC binding affinities and lipophilicities. Further investigation indicated that 2 exhibited a modestly higher level of sAPP alpha secretion than did phorbol 12,13-dibutyrate (PDBu).