5,5-bis(((tert-butyldiphenylsilyl)oxy)methyl)-3-(hydroxy(1-methyl-1H-indol-3-yl)methyl)dihydrofuran-2(3H)-one | 1056462-54-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 5,5-bis(((tert-butyldiphenylsilyl)oxy)methyl)-3-(hydroxy(1-methyl-1H-indol-3-yl)methyl)dihydrofuran-2(3H)-one
• CAS: 1056462-54-4
• 化学式: C₄₈H₅₅NO₅Si₂
• 分子量: 782.139
• InChiKey: VRHNPJSEYQVIIP-UHFFFAOYSA-N

物化性质

• 沸点：
  798.0±60.0 °C(Predicted)
• 密度：
  1.09±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.67
• 重原子数：
  56.0
• 可旋转键数：
  12.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  69.92
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  5,5-bis(((tert-butyldiphenylsilyl)oxy)methyl)-3-(hydroxy(1-methyl-1H-indol-3-yl)methyl)dihydrofuran-2(3H)-one 在 吡啶 、 四丁基氟化铵 、 甲基磺酰氯 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.5h， 生成 (E)-(2-(hydroxymethyl)-4-((1-methyl-1H-indol-3-yl)methylene)-5-oxotetrahydrofuran-2-yl)methyl 4-methoxybenzoate
  参考文献：
  名称：

  α-Arylidene Diacylglycerol-Lactones (DAG-Lactones) as Selective Ras Guanine-Releasing Protein 3 (RasGRP3) Ligands

  摘要：

  Diacylglycerol-lactones have proven to be a powerful template for the design of potent ligands targeting CI domains, the recognition motif for the cellular second messenger diacylglycerol. A major objective has been to better understand the structure activity relations distinguishing the seven families of signaling proteins that contain such domains, of which the protein kinase C (PKC) and RasGRP families are of particular interest. Here, we synthesize a series of aryl- and alkyl-substituted diacylglycerol-lactones and probe their relative selectivities for RasGRP3 versus PKC. Compound 96 showed 73-fold selectivity relative to PKC alpha 45 and 45-fold selectivity relative to PKC epsilon for in vitro binding activity. Likewise, in intact cells, compound 96 induced Ras activation, a downstream response to RasGRP stimulation, with 8-29 fold selectivity relative to PKC delta S299 phosphorylation, a measure of PKC delta stimulation.

  DOI：

  10.1021/acs.jmedchem.8b00661
• 作为产物：
  描述：

  3-吲哚甲醛 在 sodium hydride 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 3.75h， 生成 5,5-bis(((tert-butyldiphenylsilyl)oxy)methyl)-3-(hydroxy(1-methyl-1H-indol-3-yl)methyl)dihydrofuran-2(3H)-one
  参考文献：
  名称：

  α-Arylidene Diacylglycerol-Lactones (DAG-Lactones) as Selective Ras Guanine-Releasing Protein 3 (RasGRP3) Ligands

  摘要：

  Diacylglycerol-lactones have proven to be a powerful template for the design of potent ligands targeting CI domains, the recognition motif for the cellular second messenger diacylglycerol. A major objective has been to better understand the structure activity relations distinguishing the seven families of signaling proteins that contain such domains, of which the protein kinase C (PKC) and RasGRP families are of particular interest. Here, we synthesize a series of aryl- and alkyl-substituted diacylglycerol-lactones and probe their relative selectivities for RasGRP3 versus PKC. Compound 96 showed 73-fold selectivity relative to PKC alpha 45 and 45-fold selectivity relative to PKC epsilon for in vitro binding activity. Likewise, in intact cells, compound 96 induced Ras activation, a downstream response to RasGRP stimulation, with 8-29 fold selectivity relative to PKC delta S299 phosphorylation, a measure of PKC delta stimulation.

  DOI：

  10.1021/acs.jmedchem.8b00661

文献信息

• Conformationally Constrained Analogues of Diacylglycerol. 30. An Investigation of Diacylglycerol-lactones Containing Heteroaryl Groups Reveals Compounds with High Selectivity for Ras Guanyl Nucleotide-Releasing Proteins
  作者：Saïd El Kazzouli、Nancy E. Lewin、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm800380b

  日期：2008.9.11

  Using a diacylglycerol-lactone (DAG-lactone) template previously developed in our laboratory as a scaffold with high binding affinity for C I domains, we describe herein a series of novel DAG-lactones containing heterocyclic moieties (pyridines, quinolines, and indoles) as alpha-arylidene fragments. Some of the DAG-lactones obtained show selective binding to RasGRP3 as compared to PKC alpha by more than 2 orders of magnitude and possess subnanomolar affinities. Because activated C1 domains bound to their ligands (DAG or DAG-lactones) insert into membranes, the lipid composition of membranes (cellular, nuclear, and those of internal organelles) is an important determinant for specificity. Therefore, reaching a proper hydrophilic/lipophilic balance for these molecules is critical. This was achieved by carefully selecting partnering acyl fragments for the DAG-lactones with the appropriate lipophilicity. The results clearly show that the combination of chemical and physical properties in these molecules needs to be perfectly balanced to achieve the desired specificity.