5-[(4-methoxyphenoxy)methyl]-4,4-dimethyl-3-[4-methyl-3-(methylethyl)pentylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one | 1026254-52-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-[(4-methoxyphenoxy)methyl]-4,4-dimethyl-3-[4-methyl-3-(methylethyl)pentylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one
• 英文别名: (3Z)-5-[(4-methoxyphenoxy)methyl]-4,4-dimethyl-3-(4-methyl-3-propan-2-ylpentylidene)-5-(phenylmethoxymethyl)oxolan-2-one
• CAS: 1026254-52-3
• 化学式: C₃₁H₄₂O₅
• 分子量: 494.671
• InChiKey: DYWRCQKPYYWMGA-MTDXEUNCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  54
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-[(4-methoxyphenoxy)methyl]-4,4-dimethyl-3-[4-methyl-3-(methylethyl)pentylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one 在 吡啶 、 4-二甲氨基吡啶 、 ammonium cerium(IV) nitrate 、 三氯化硼 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 9.5h， 生成 2,2-Dimethyl-propionic acid 2-hydroxymethyl-4-[3-isopropyl-4-methyl-pent-(Z)-ylidene]-3,3-dimethyl-5-oxo-tetrahydro-furan-2-ylmethyl ester
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol (DAG). 23. Hydrophobic Ligand−Protein Interactions versus Ligand−Lipid Interactions of DAG-Lactones with Protein Kinase C (PK-C)

  摘要：

  The constrained glycerol backbone of DAG-lactones, when combined with highly branched alkyl chains, has engendered a series of DAG-lactone ligands capable of binding protein kinase C (PK-C) with affinities that approximate those of phorbol esters. These branched chains not only appear to be involved in making important hydrophobic contacts with the protein (specific interactions) but also provide adequate lipophilicity to facilitate partitioning into the lipid-rich membrane environment (nonspecific interactions). With the idea of minimizing the nonspecific interactions without reducing lipophilicity, the present work explores the strategy of relocating lipophilicity from the side chain to the lactone "core". Such a transfer of lipophilicity, exemplified by compounds I and 3, was conceived to allow the new hydrophobic groups on the lactone to engage in specific hydrophobic contacts inside the binding pocket without any expectation of interfering with the hydrogen-bonding network of the DAG-lactone pharmacophore. Surprisingly, both (E)-3 and (Z)-3 showed a significant decrease in binding affinity. From the molecular docking studies performed with the new ligands, we conclude that the binding pocket of the C I domain of PK-C is sterically restricted and prevents the methyl groups at the C-3 position of the lactone from engaging in productive hydrophobic contacts with the receptor.

  DOI：

  10.1021/jm049723+
• 作为产物：
  描述：

  1-(4-甲氧基苯氧基)-3-苯基甲氧基丙烷-2-酮 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 四丙基高钌酸铵 、 偶氮二异丁腈 、 4 A molecular sieve 、 三正丁基氢锡 、 sodium hydride 、 N-甲基吗啉氧化物 、 三乙胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正庚烷 、 二氯甲烷 、 乙基苯 、 N,N-二甲基甲酰胺 、 乙腈 、 苯 为溶剂， 反应 36.5h， 生成 5-[(4-methoxyphenoxy)methyl]-4,4-dimethyl-3-[4-methyl-3-(methylethyl)pentylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol (DAG). 23. Hydrophobic Ligand−Protein Interactions versus Ligand−Lipid Interactions of DAG-Lactones with Protein Kinase C (PK-C)

  摘要：

  The constrained glycerol backbone of DAG-lactones, when combined with highly branched alkyl chains, has engendered a series of DAG-lactone ligands capable of binding protein kinase C (PK-C) with affinities that approximate those of phorbol esters. These branched chains not only appear to be involved in making important hydrophobic contacts with the protein (specific interactions) but also provide adequate lipophilicity to facilitate partitioning into the lipid-rich membrane environment (nonspecific interactions). With the idea of minimizing the nonspecific interactions without reducing lipophilicity, the present work explores the strategy of relocating lipophilicity from the side chain to the lactone "core". Such a transfer of lipophilicity, exemplified by compounds I and 3, was conceived to allow the new hydrophobic groups on the lactone to engage in specific hydrophobic contacts inside the binding pocket without any expectation of interfering with the hydrogen-bonding network of the DAG-lactone pharmacophore. Surprisingly, both (E)-3 and (Z)-3 showed a significant decrease in binding affinity. From the molecular docking studies performed with the new ligands, we conclude that the binding pocket of the C I domain of PK-C is sterically restricted and prevents the methyl groups at the C-3 position of the lactone from engaging in productive hydrophobic contacts with the receptor.

  DOI：

  10.1021/jm049723+

文献信息

• Conformationally Constrained Analogues of Diacylglycerol (DAG). 23. Hydrophobic Ligand−Protein Interactions versus Ligand−Lipid Interactions of DAG-Lactones with Protein Kinase C (PK-C)
  作者：Hirokazu Tamamura、Dina M. Sigano、Nancy E. Lewin、Megan L. Peach、Marc C. Nicklaus、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm049723+

  日期：2004.9.1

  The constrained glycerol backbone of DAG-lactones, when combined with highly branched alkyl chains, has engendered a series of DAG-lactone ligands capable of binding protein kinase C (PK-C) with affinities that approximate those of phorbol esters. These branched chains not only appear to be involved in making important hydrophobic contacts with the protein (specific interactions) but also provide adequate lipophilicity to facilitate partitioning into the lipid-rich membrane environment (nonspecific interactions). With the idea of minimizing the nonspecific interactions without reducing lipophilicity, the present work explores the strategy of relocating lipophilicity from the side chain to the lactone "core". Such a transfer of lipophilicity, exemplified by compounds I and 3, was conceived to allow the new hydrophobic groups on the lactone to engage in specific hydrophobic contacts inside the binding pocket without any expectation of interfering with the hydrogen-bonding network of the DAG-lactone pharmacophore. Surprisingly, both (E)-3 and (Z)-3 showed a significant decrease in binding affinity. From the molecular docking studies performed with the new ligands, we conclude that the binding pocket of the C I domain of PK-C is sterically restricted and prevents the methyl groups at the C-3 position of the lactone from engaging in productive hydrophobic contacts with the receptor.