(3S,5S)-5-(1-{(1S,3R,10R,13R,17R)-1,3-bis[(methoxycarbonyl)oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl}ethyl)-2-methylnonan-3-yl (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate | 1127352-51-5

• 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: (3S,5S)-5-(1-{(1S,3R,10R,13R,17R)-1,3-bis[(methoxycarbonyl)oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl}ethyl)-2-methylnonan-3-yl (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
• 英文别名: [(3S,5S)-5-[(1R)-1-[(1S,3R,9S,10R,13R,14R,17R)-1,3-bis(methoxycarbonyloxy)-10,13-dimethyl-2,3,4,9,11,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl]ethyl]-2-methylnonan-3-yl] (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
• CAS: 1127352-51-5
• 化学式: C₄₅H₆₃F₃O₉
• 分子量: 804.985
• InChiKey: CCEDXKOFBAHRAL-OUGRDYOHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  12.6
• 重原子数：
  57
• 可旋转键数：
  19
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  107
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  (1α,3β,22S,24S)-bis[(methoxycarbonyl)oxy]-22-butylcholesta-5,7-dien-24-ol 、 (R)-methoxytrifluoromethylphenylacetyl chloride 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以97.1%的产率得到(3S,5S)-5-(1-{(1S,3R,10R,13R,17R)-1,3-bis[(methoxycarbonyl)oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl}ethyl)-2-methylnonan-3-yl (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
  参考文献：
  名称：

  A New Class of Vitamin D Analogues that Induce Structural Rearrangement of the Ligand-Binding Pocket of the Receptor

  摘要：

  To identify novel vitamin D receptor (VDR) ligands that induce a novel architecture within the ligand-binding pocket (LBP), we have investigated eight 22-butyl-1 alpha,24-dihydroxyvitamin D-3 derivatives (3-10), all having a butyl group as the branched alkyl side chain. We found that the 22S-butyl-20-epi-25,26,27-trinorvitamin D derivative 5 was a potent VDR agonist, whereas the corresponding compound 4 with the natural configuration at C(20) was a potent VDR antagonist. Analogues with the full vitamin D3 side chain were less potent agonist, and whether they were agonists or antagonists depended on the 24-configuration. X-ray crystal structures demonstrated that the VDR-LBD accommodating the potent agonist 5 has an architecture wherein the lower side and the helix 11 side of the LBP is simply expanded relative to the canonical active-VDR situation; in contrast, the potent antagonist 4 induces an extra cavity to accommodate the branched moiety. This is the first report of a VDR antagonist that generates a new cavity to alter the canonical pocket structure of the ligand occupied VDR.

  DOI：

  10.1021/jm8014348

文献信息

• A New Class of Vitamin D Analogues that Induce Structural Rearrangement of the Ligand-Binding Pocket of the Receptor
  作者：Yuka Inaba、Nobuko Yoshimoto、Yuta Sakamaki、Makoto Nakabayashi、Teikichi Ikura、Hirokazu Tamamura、Nobutoshi Ito、Masato Shimizu、Keiko Yamamoto

  DOI：10.1021/jm8014348

  日期：2009.3.12

  To identify novel vitamin D receptor (VDR) ligands that induce a novel architecture within the ligand-binding pocket (LBP), we have investigated eight 22-butyl-1 alpha,24-dihydroxyvitamin D-3 derivatives (3-10), all having a butyl group as the branched alkyl side chain. We found that the 22S-butyl-20-epi-25,26,27-trinorvitamin D derivative 5 was a potent VDR agonist, whereas the corresponding compound 4 with the natural configuration at C(20) was a potent VDR antagonist. Analogues with the full vitamin D3 side chain were less potent agonist, and whether they were agonists or antagonists depended on the 24-configuration. X-ray crystal structures demonstrated that the VDR-LBD accommodating the potent agonist 5 has an architecture wherein the lower side and the helix 11 side of the LBP is simply expanded relative to the canonical active-VDR situation; in contrast, the potent antagonist 4 induces an extra cavity to accommodate the branched moiety. This is the first report of a VDR antagonist that generates a new cavity to alter the canonical pocket structure of the ligand occupied VDR.