methyl 3-[(1R,4aR,4bS,8aS,10aS)-4b,8,8,10a-tetramethyl-2-oxo-1,3,4,4a,5,6,7,8a,9,10-decahydrophenanthren-1-yl]propanoate | 112575-99-2

• 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: methyl 3-[(1R,4aR,4bS,8aS,10aS)-4b,8,8,10a-tetramethyl-2-oxo-1,3,4,4a,5,6,7,8a,9,10-decahydrophenanthren-1-yl]propanoate
• CAS: 112575-99-2
• 化学式: C₂₂H₃₆O₃
• 分子量: 348.526
• InChiKey: BIPDREOVFWTNOY-AHIJYVNXSA-N

物化性质

• 沸点：
  420.8±18.0 °C(predicted)
• 密度：
  0.998±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 3-[(1R,4aR,4bS,8aS,10aS)-4b,8,8,10a-tetramethyl-2-oxo-1,3,4,4a,5,6,7,8a,9,10-decahydrophenanthren-1-yl]propanoate 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 15.0h， 以64%的产率得到(1R,2S,4aR,4bS,8aS,10aS)-1-(3-Hydroxy-propyl)-4b,8,8,10a-tetramethyl-tetradecahydro-phenanthren-2-ol
  参考文献：
  名称：

  Chemistry and revised structure of suvanine

  摘要：

  DOI：

  10.1021/jo00238a017
• 作为产物：
  描述：

  suvanine 在 臭氧 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 3.34h， 生成 methyl 3-[(1R,4aR,4bS,8aS,10aS)-4b,8,8,10a-tetramethyl-2-oxo-1,3,4,4a,5,6,7,8a,9,10-decahydrophenanthren-1-yl]propanoate
  参考文献：
  名称：

  Binding Mechanism of the Farnesoid X Receptor Marine Antagonist Suvanine Reveals a Strategy To Forestall Drug Modulation on Nuclear Receptors. Design, Synthesis, and Biological Evaluation of Novel Ligands

  摘要：

  Here, we report suvanine, a marine sponge sesterterpene, as an antagonist of the mammalian bile acid sensor farnesoid-X-receptor (FXR). Using suvanine as a template, we shed light on the molecular bases of FXR antagonism, identifying the essential conformational changes responsible for the transition from the agonist to the antagonist form. Molecular characterization of the nuclear corepressor NCoR and coactivator Src-1 revealed that receptor conformational changes are associated with a specific dynamic of recruitment of these cofactors to the promoter of OST alpha, a FXR regulated gene. Using suvanine as a novel hit, a library of semisynthetic derivatives has been designed and prepared, leading to pharmacological profiles ranging from agonism to antagonism toward FXR. Deep pharmacological evaluation demonstrated that derivative 19 represents a new chemotype of FXR modulator, whereas alcohol 6, with a simplified molecular scaffold, exhibits excellent antagonistic activity.

  DOI：

  10.1021/jm400419e

文献信息

• Chemistry and revised structure of suvanine
  作者：Lawrence V. Manes、Phillip Crews、Michael R. Kernan、D. John Faulkner、Frank R. Fronczek、Richard D. Gandour

  DOI：10.1021/jo00238a017

  日期：1988.2
• Binding Mechanism of the Farnesoid X Receptor Marine Antagonist Suvanine Reveals a Strategy To Forestall Drug Modulation on Nuclear Receptors. Design, Synthesis, and Biological Evaluation of Novel Ligands
  作者：Francesco Saverio Di Leva、Carmen Festa、Claudio D’Amore、Simona De Marino、Barbara Renga、Maria Valeria D’Auria、Ettore Novellino、Vittorio Limongelli、Angela Zampella、Stefano Fiorucci

  DOI：10.1021/jm400419e

  日期：2013.6.13

  Here, we report suvanine, a marine sponge sesterterpene, as an antagonist of the mammalian bile acid sensor farnesoid-X-receptor (FXR). Using suvanine as a template, we shed light on the molecular bases of FXR antagonism, identifying the essential conformational changes responsible for the transition from the agonist to the antagonist form. Molecular characterization of the nuclear corepressor NCoR and coactivator Src-1 revealed that receptor conformational changes are associated with a specific dynamic of recruitment of these cofactors to the promoter of OST alpha, a FXR regulated gene. Using suvanine as a novel hit, a library of semisynthetic derivatives has been designed and prepared, leading to pharmacological profiles ranging from agonism to antagonism toward FXR. Deep pharmacological evaluation demonstrated that derivative 19 represents a new chemotype of FXR modulator, whereas alcohol 6, with a simplified molecular scaffold, exhibits excellent antagonistic activity.