1-(3-isopropyl-4-methylpentanoyl)-3-benzyl-sn-glycerol | 274911-01-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 甘油脂
• 英文名称: 1-(3-isopropyl-4-methylpentanoyl)-3-benzyl-sn-glycerol
• 英文别名: [(2S)-2-hydroxy-3-phenylmethoxypropyl] 4-methyl-3-propan-2-ylpentanoate
• CAS: 274911-01-2
• 化学式: C₁₉H₃₀O₄
• 分子量: 322.445
• InChiKey: UUNBRHVFXGLDCK-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  23
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(3-isopropyl-4-methylpentanoyl)-3-benzyl-sn-glycerol 在 吡啶 、 4-二甲氨基吡啶 、 三氯化硼 作用下， 以 二氯甲烷 为溶剂， 生成 3-Isopropyl-4-methyl-pentanoic acid 3-hydroxy-2-(3-methyl-but-2-enoyloxy)-propyl ester
  参考文献：
  名称：

  An Optimized Protein Kinase C Activating Diacylglycerol Combining High Binding Affinity (K_i) with Reduced Lipophilicity (log P)

  摘要：

  A small, focused combinatorial library encompassing all possible permutations of acyl branched alkyl chains-small and large, saturated and unsaturated-was generated from the active diacylglycerol enantiomer (S-DAG) to help identify the analogue with the highest binding affinity (lowest K-i) for protein kinase C (PK-C) combined with the minimum lipophilicity (log P). The selected ligand (3B) activated PK-C more effectively than sn-1,2-dioctanoylglycerol (diC8) despite being 1.4 log units more hydrophilic. Compound 3B indeed represents the most potent, hydrophilic DAG ligand to date. With the help of a green fluorescent protein (GFP)tagged PK-C alpha, 3B was able to translocate the full length protein to the membrane with an optimal dose of 100 muM in CHO-K1 cells, while diC8 failed to achieve translocation even at doses 3-fold higher. Molecular modeling of 3B into an empty C1b domain of PK-C delta clearly showed the existence of a preferred binding orientation. In addition, molecular dynamic simulations suggest that binding discrimination could result from a favorable van der Waals (VDW) interaction between the large, branched sn-1 acyl group of 3B and the aromatic rings of Trp252 (PK-C delta) or Tyr252 (PK-C alpha). The DAG analogue of 3B in which the acyl groups are reversed (2C) showed a decrease in binding affinity reflecting the capacity of PK-C to effectively discriminate between alternative orientations of the acyl chains.

  DOI：

  10.1021/jm010052e
• 作为产物：
  描述：

  (R)-(+)-3-苄氧基-1,2-丙二醇 、 4-methyl-3-(1-methylethyl)pentanoyl chloride 在 二正丁基氧化锡 作用下， 以 甲苯 为溶剂， 反应 4.5h， 以87%的产率得到1-(3-isopropyl-4-methylpentanoyl)-3-benzyl-sn-glycerol
  参考文献：
  名称：

  An Optimized Protein Kinase C Activating Diacylglycerol Combining High Binding Affinity (K_i) with Reduced Lipophilicity (log P)

  摘要：

  A small, focused combinatorial library encompassing all possible permutations of acyl branched alkyl chains-small and large, saturated and unsaturated-was generated from the active diacylglycerol enantiomer (S-DAG) to help identify the analogue with the highest binding affinity (lowest K-i) for protein kinase C (PK-C) combined with the minimum lipophilicity (log P). The selected ligand (3B) activated PK-C more effectively than sn-1,2-dioctanoylglycerol (diC8) despite being 1.4 log units more hydrophilic. Compound 3B indeed represents the most potent, hydrophilic DAG ligand to date. With the help of a green fluorescent protein (GFP)tagged PK-C alpha, 3B was able to translocate the full length protein to the membrane with an optimal dose of 100 muM in CHO-K1 cells, while diC8 failed to achieve translocation even at doses 3-fold higher. Molecular modeling of 3B into an empty C1b domain of PK-C delta clearly showed the existence of a preferred binding orientation. In addition, molecular dynamic simulations suggest that binding discrimination could result from a favorable van der Waals (VDW) interaction between the large, branched sn-1 acyl group of 3B and the aromatic rings of Trp252 (PK-C delta) or Tyr252 (PK-C alpha). The DAG analogue of 3B in which the acyl groups are reversed (2C) showed a decrease in binding affinity reflecting the capacity of PK-C to effectively discriminate between alternative orientations of the acyl chains.

  DOI：

  10.1021/jm010052e

文献信息

• Diacylglycerols with lipophilically equivalent branched acyl chains display high affinity for protein kinase C (PK-C). A direct measure of the effect of constraining the glycerol backbone in DAG lactones
  作者：Kassoum Nacro、Bruno Bienfait、Nancy E. Lewin、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1016/s0960-894x(00)00070-6

  日期：2000.4

  New synthetic diacylglycerols (DAGs) with equivalent branched acyl chains were compared with commercially available DAGs as PK-C ligands. The results support the view that there is a minimal lipophilic requirement provided by the equivalent acyl groups that results in high binding affinity. Locking the glycerol backbone of the most potent DAG into a five-member lactone resulted in a 10-fold increase in potency. Published by Elsevier Science Ltd.
• An Optimized Protein Kinase C Activating Diacylglycerol Combining High Binding Affinity (<i>K</i>_i) with Reduced Lipophilicity (log P)
  作者：Kassoum Nacro、Dina M. Sigano、Shunqi Yan、Marc C. Nicklaus、Larry L. Pearce、Nancy E. Lewin、Susan H. Garfield、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm010052e

  日期：2001.6.1

  A small, focused combinatorial library encompassing all possible permutations of acyl branched alkyl chains-small and large, saturated and unsaturated-was generated from the active diacylglycerol enantiomer (S-DAG) to help identify the analogue with the highest binding affinity (lowest K-i) for protein kinase C (PK-C) combined with the minimum lipophilicity (log P). The selected ligand (3B) activated PK-C more effectively than sn-1,2-dioctanoylglycerol (diC8) despite being 1.4 log units more hydrophilic. Compound 3B indeed represents the most potent, hydrophilic DAG ligand to date. With the help of a green fluorescent protein (GFP)tagged PK-C alpha, 3B was able to translocate the full length protein to the membrane with an optimal dose of 100 muM in CHO-K1 cells, while diC8 failed to achieve translocation even at doses 3-fold higher. Molecular modeling of 3B into an empty C1b domain of PK-C delta clearly showed the existence of a preferred binding orientation. In addition, molecular dynamic simulations suggest that binding discrimination could result from a favorable van der Waals (VDW) interaction between the large, branched sn-1 acyl group of 3B and the aromatic rings of Trp252 (PK-C delta) or Tyr252 (PK-C alpha). The DAG analogue of 3B in which the acyl groups are reversed (2C) showed a decrease in binding affinity reflecting the capacity of PK-C to effectively discriminate between alternative orientations of the acyl chains.