(4aR,4bS,6aS,7S,9aS,9bS,9cS,10aS,10bR)-7-((R)-1-((R)-4,5-dimethyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-1-hydroxyethyl)-10b-hydroxy-4a,6a-dimethylhexadecahydro-4H-cyclopenta[1,2]phenanthro[9,10-b]oxiren-4-one | 33428-64-7

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: (4aR,4bS,6aS,7S,9aS,9bS,9cS,10aS,10bR)-7-((R)-1-((R)-4,5-dimethyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-1-hydroxyethyl)-10b-hydroxy-4a,6a-dimethylhexadecahydro-4H-cyclopenta[1,2]phenanthro[9,10-b]oxiren-4-one
• CAS: 33428-64-7
• 化学式: C₂₈H₄₀O₆
• 分子量: 472.622
• InChiKey: FGQLZNFOQRNAMA-SFQAJKIESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.72
• 重原子数：
  34.0
• 可旋转键数：
  2.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  96.36
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (4aR,4bS,6aS,7S,9aS,9bS,9cS,10aS,10bR)-7-((R)-1-((R)-4,5-dimethyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-1-hydroxyethyl)-10b-hydroxy-4a,6a-dimethylhexadecahydro-4H-cyclopenta[1,2]phenanthro[9,10-b]oxiren-4-one 、 O-2-丙炔羟胺盐酸盐 在 吡啶 作用下， 反应 7.0h， 以75%的产率得到(R)-6-((R)-1-hydroxy-1-((4aS,4bS,6aS,7S,9aS,9bS,9cS,10aS,10bR,E)-10b-hydroxy-4a,6a-dimethyl-4-((prop-2-yn-1-yloxy)imino)hexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-b]oxiren-7-yl)ethyl)-3,4-dimethyl-5,6-dihydro-2H-pyran-2-one
  参考文献：
  名称：

  Profiling withanolide A for therapeutic targets in neurodegenerative diseases

  摘要：

  To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-kappa B, TR alpha, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.

  DOI：

  10.1016/j.bmc.2019.03.022
• 作为产物：
  描述：

  睡茄素A 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 3.0h， 以100%的产率得到(4aR,4bS,6aS,7S,9aS,9bS,9cS,10aS,10bR)-7-((R)-1-((R)-4,5-dimethyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-1-hydroxyethyl)-10b-hydroxy-4a,6a-dimethylhexadecahydro-4H-cyclopenta[1,2]phenanthro[9,10-b]oxiren-4-one
  参考文献：
  名称：

  Profiling withanolide A for therapeutic targets in neurodegenerative diseases

  摘要：

  To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-kappa B, TR alpha, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.

  DOI：

  10.1016/j.bmc.2019.03.022