(4R)-4-((3R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-(6-(3-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)thioureido)hexyl)pentanamide

• 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: (4R)-4-((3R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-(6-(3-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)thioureido)hexyl)pentanamide
• 英文别名: FITC-hyodeoxycholic acid；(4R)-4-[(3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-N-[6-[(3',6'-dihydroxy-3-oxospiro[2-benzofuran-1,9'-xanthene]-5-yl)carbamothioylamino]hexyl]pentanamide
• 化学式: C₅₁H₆₅N₃O₈S
• 分子量: 880.158
• InChiKey: MFJKSCWIKMCTMG-RGOSNDNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.9
• 重原子数：
  63
• 可旋转键数：
  12
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  202
• 氢给体数：
  7
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  N-Boc-1,6-己二胺 、 猪去氧胆酸 在 盐酸 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (4R)-4-((3R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-(6-(3-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-5-yl)thioureido)hexyl)pentanamide
  参考文献：
  名称：

  Identify liver X receptor β modulator building blocks by developing a fluorescence polarization-based competition assay

  摘要：

  The liver X receptors (LXRs) of the nuclear receptor family are promising therapeutic targets of multiple diseases like lipid disorders, chronic inflammation, as well as different human cancers. To date, no LXR agonists or antagonists can be used in clinics, emphasizing the importance for discovering new LXR modulators. Fragment-based lead discovery (FBLD) is powerful for designing new scaffolds and new mechanistic drugs, but fragment screening has not been applied to LXRs yet, which might be due to the lack of a specific fragment screening method against the dynamic and hydrophobic ligand binding domain (LBD) of LXRs. Herein, a series of fluorescent tracers were designed, synthesized and tested. The tracer based on hyodeoxycholic acid exhibited a good capability for competitively detecting the ligand binding of LXR beta using a fluorescence polarization approach. Then, 1074 fragments were screened against the LBD of LXR beta (LXR beta-LBD), resulting in 27 binding hits. These fragment hits were further tested using the co-activator recruitment assay and reporter gene assay, and efforts in X-ray crystallography fortunately solved a co-crystal structure of LXR beta-LBD with the fragment F3 (tert-buty1-7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate). The fluorescence-based fragment screening tool and the newly identified LXR beta binding fragments provide the basis for developing novel LXR beta modulators. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.06.011

文献信息

• Identify liver X receptor β modulator building blocks by developing a fluorescence polarization-based competition assay
  作者：Zizhen Zhang、Hao Chen、Ziyang Chen、Peng Ding、Yingchen Ju、Qiong Gu、Jun Xu、Huihao Zhou

  DOI：10.1016/j.ejmech.2019.06.011

  日期：2019.9

  The liver X receptors (LXRs) of the nuclear receptor family are promising therapeutic targets of multiple diseases like lipid disorders, chronic inflammation, as well as different human cancers. To date, no LXR agonists or antagonists can be used in clinics, emphasizing the importance for discovering new LXR modulators. Fragment-based lead discovery (FBLD) is powerful for designing new scaffolds and new mechanistic drugs, but fragment screening has not been applied to LXRs yet, which might be due to the lack of a specific fragment screening method against the dynamic and hydrophobic ligand binding domain (LBD) of LXRs. Herein, a series of fluorescent tracers were designed, synthesized and tested. The tracer based on hyodeoxycholic acid exhibited a good capability for competitively detecting the ligand binding of LXR beta using a fluorescence polarization approach. Then, 1074 fragments were screened against the LBD of LXR beta (LXR beta-LBD), resulting in 27 binding hits. These fragment hits were further tested using the co-activator recruitment assay and reporter gene assay, and efforts in X-ray crystallography fortunately solved a co-crystal structure of LXR beta-LBD with the fragment F3 (tert-buty1-7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate). The fluorescence-based fragment screening tool and the newly identified LXR beta binding fragments provide the basis for developing novel LXR beta modulators. (C) 2019 Elsevier Masson SAS. All rights reserved.