methyl (R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-hydroxy-7,12-dimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate | 360042-72-4

• 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 (R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-hydroxy-7,12-dimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate
• 英文别名: methyl 7,12-dimethylcholate；methyl (4R)-4-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-hydroxy-7,12-dimethoxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate
• CAS: 360042-72-4
• 化学式: C₂₇H₄₆O₅
• 分子量: 450.659
• InChiKey: BARJOPHICVSDNK-OCCHXLOTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-hydroxy-7,12-dimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate 在 甲醇 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 8.0h， 生成 (R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-hydroxy-7,12-dimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-phenylpentanamide
  参考文献：
  名称：

  发现新型胆酸衍生物作为 G 蛋白偶联胆汁酸受体的高效激动剂

  摘要：

  本研究设计合成了14种新的胆酸（CA）衍生物，GloSensor cAMP积累试验表明所有衍生物均可激活武田G蛋白偶联受体5（TGR5）。CA 中 7-和 12-羟基的甲基化显着增加了新衍生物的 TGR5 激动作用。例如，7,12-二甲氧基衍生物B1对 TGR5 的效力比 7,12-二羟基衍生物A1高 78 倍，比 CA 本身高 258 倍。另一方面，A1正向调节 TGR5 中的鹅去氧胆酸 (CDCA) 功能活性，而B1没有显示出类似的活性。分子对接实验表明A1TGR5的12-OH与氨基酸Thr131之间形成氢键，这对其变构特性具有重要意义。然而，CA（衍生物B1 ）中 12-羟基的甲基化破坏了这个关键的氢键。因此，游离的 12-羟基对于 TGR5 变构激动中的 CA 衍生物是必不可少的。总体而言，我们发现了一种高效的 TGR5 激动剂B1，可用作进一步研究的先导化合物。

  DOI：

  10.1016/j.bioorg.2021.105588
• 作为产物：
  描述：

  胆酸甲酯 在 吡啶 、 咪唑 、 2,6-二叔丁基吡啶 、 四丁基氟化铵 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 36.0h， 生成 methyl (R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-hydroxy-7,12-dimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate
  参考文献：
  名称：

  发现新型胆酸衍生物作为 G 蛋白偶联胆汁酸受体的高效激动剂

  摘要：

  本研究设计合成了14种新的胆酸（CA）衍生物，GloSensor cAMP积累试验表明所有衍生物均可激活武田G蛋白偶联受体5（TGR5）。CA 中 7-和 12-羟基的甲基化显着增加了新衍生物的 TGR5 激动作用。例如，7,12-二甲氧基衍生物B1对 TGR5 的效力比 7,12-二羟基衍生物A1高 78 倍，比 CA 本身高 258 倍。另一方面，A1正向调节 TGR5 中的鹅去氧胆酸 (CDCA) 功能活性，而B1没有显示出类似的活性。分子对接实验表明A1TGR5的12-OH与氨基酸Thr131之间形成氢键，这对其变构特性具有重要意义。然而，CA（衍生物B1 ）中 12-羟基的甲基化破坏了这个关键的氢键。因此，游离的 12-羟基对于 TGR5 变构激动中的 CA 衍生物是必不可少的。总体而言，我们发现了一种高效的 TGR5 激动剂B1，可用作进一步研究的先导化合物。

  DOI：

  10.1016/j.bioorg.2021.105588

文献信息

• Transmembrane Ion Channels Constructed of Cholic Acid Derivatives
  作者：Yoshiaki Kobuke、Takeshi Nagatani

  DOI：10.1021/jo010208i

  日期：2001.7.1

  A new class of supramolecular transmembrane ion channels was prepared by linking two amphiphilic cholic acid methyl ethers through biscarbamate bonds to afford bis(7,12-dimethyl-24-carboxy-3-cholanyl)-N,N'-xylylene dicarbamate 2 and bis[7,12-dimethyl-24-(N,N,N-trimethylethanaminium-2-carboxylate)-3-cholanyl]-N,N'-xylylene dicarbamate dichloride 3. When incorporated into a planar bilayer membrane, both compounds showed stable (lasting 10 ms to 10 s) single ion channel currents. Only limited numbers of relatively small conductances were characterized for these channels (5-20 pS for 2 and 5-10 pS for 3, 10 and 17 pS for 2, and 9 pS for 3 in particular). Both channels were cation selective, and permeability ratios of potassium cation to chloride anion were 17 and 7.9 for 2 and 3, respectively, reflecting the difference in ionic species of the headgroup. Both channels 2 and 3 showed significant potassium selectivity over sodium by a factor of 3.1 and 3.2, respectively. No Li+ currents were observed for 2, showing sharp discrimination between Na+ or K+.
• Artificial Ion Channels Showing Rectified Current Behavior
  作者：Chigusa Goto、Mika Yamamura、Akiharu Satake、Yoshiaki Kobuke

  DOI：10.1021/ja010761h

  日期：2001.12.1

  Voltage-dependent artificial ion channels 3 and 4 were synthesized. Two cholic acid derivatives were connected through a m-xylylene dicarbamate unit at 3-hydroxyl groups. Asymmetries were introduced by terminal hydrophilic groups, carboxylic acid and phosphoric acid for 3 and hydroxyl and carboxylic acid for 4. Under basic conditions, these headgroups in 3 and 4 are expected to be dissociate into -1/-2 (pH 8.2) and 0/-1 (pH 7.2), respectively. Single ion channel properties were examined by a planar bilayer lipid membrane method under symmetrical 500 mM KCl at pH 8.2 or 7.2. When 3 and 4 were introduced into the bilayer membrane under application of positive voltage (a positive-shift method), the current values at positive applied voltage were larger than the corresponding ones at the negative applied voltage. The current-voltage plots were fitted by curves through a zero point to show clear rectification properties. The direction of rectification could be controlled by positive- or negative-shift methods. Vectorial alignment of terminal headgroup charges by the voltage-shift incorporation is essential for giving voltage-dependent rectified ion channels.