(E)-3-{2-Hydroxymethyl-4-[3-isobutyl-5-methyl-hex-(Z)-ylidene]-5-oxo-tetrahydro-furan-2-yl}-acrylic acid tert-butyl ester

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (E)-3-{2-Hydroxymethyl-4-[3-isobutyl-5-methyl-hex-(Z)-ylidene]-5-oxo-tetrahydro-furan-2-yl}-acrylic acid tert-butyl ester
• 英文别名: 5-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]-5-hydroxymethyl-3-[(Z)-3-isobutyl-5-methylhexylidene]tetrahydro-2-furanone；tert-butyl (E)-3-[(4Z)-2-(hydroxymethyl)-4-[5-methyl-3-(2-methylpropyl)hexylidene]-5-oxooxolan-2-yl]prop-2-enoate
• 化学式: C₂₃H₃₈O₅
• 分子量: 394.552
• InChiKey: AKVCUOZKJVRCQK-PQONSAHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-[(4-methoxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydrofuran-2-one 在 草酰氯 、 ammonium cerium(IV) nitrate 、 三氯化硼 、 二甲基亚砜 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 33.83h， 生成 (E)-3-{2-Hydroxymethyl-4-[3-isobutyl-5-methyl-hex-(Z)-ylidene]-5-oxo-tetrahydro-furan-2-yl}-acrylic acid tert-butyl 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

文献信息

• 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).