N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-2-(2-tridecylcycloprop-1-enyl)ethyl]octanamide | 363174-07-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-2-(2-tridecylcycloprop-1-enyl)ethyl]octanamide
• 英文别名: GT11；N-[(1R,2S)-1,3-dihydroxy-1-(2-tridecylcyclopropen-1-yl)propan-2-yl]octanamide
• CAS: 363174-07-6
• 化学式: C₂₇H₅₁NO₃
• 分子量: 437.707
• InChiKey: WHXCOSOMEQMKRN-AHKZPQOWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.8
• 重原子数：
  31
• 可旋转键数：
  22
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-2-(2-tridecylcycloprop-1-enyl)ethyl]octanamide 在 4-甲基苯磺酸吡啶 、 sodium hydride 作用下， 以 四氢呋喃 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 24.0h， 生成 (4'R,5'S)-N-[2,2-dimethyl-4-(2-tridecylcyclopropen-1-yl)-1,3-dioxan-5-yl]-N-methyloctanamide
  参考文献：
  名称：

  Analogs of the dihydroceramide desaturase inhibitor GT11 modified at the amide function: synthesis and biological activities

  摘要：

  二氢酰胺去饱和酶是神经酰胺新合成中的最后一个酶。含环丙烯的鞘脂GT11是二氢酰胺去饱和酶的竞争性抑制剂。本文报告了对GT11酰胺键的化学修饰的生物学效应。N-甲基取代或将酰胺α-羰基亚甲基替换为氧会导致化合物失活。相比之下，GT11的脲化合物（3）和硫脲化合物（4）以及三种α-酮酰胺（5–7）确实抑制了N-辛酰鞘氨醇向N-辛酰神经酰胺的去饱和，尽管其效力显著低于GT11。此外，α-酮酰胺5–7也以相似的效力抑制酸性神经酰胺酶（IC50 52–83 µM）。这些化合物对中性/碱性神经酰胺酶的抑制需要约20倍的更高浓度。文中讨论了这些化合物的结构-活性关系和生物学兴趣。

  DOI：

  10.1039/b510198k
• 作为产物：
  描述：

  1,1,2-三溴-2-十三烷基环丙烷 在 吡啶 、 2,6-二甲基吡啶 、 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 氯仿 为溶剂， 反应 3.25h， 生成 N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-2-(2-tridecylcycloprop-1-enyl)ethyl]octanamide
  参考文献：
  名称：

  Synthesis of Cyclopropene Analogues of Ceramide and Their Effect on Dihydroceramide Desaturase

  摘要：

  The synthesis of several analogues of the N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first reported inhibitor of dihydroceramide desaturase, as well as their effects on this enzyme, are described. Modifications of the parent structure include variations on the cyclopropene ring, the N-acyl chain length, the configuration of the stereocenters, and the hydroxyl group at C1. The key intermediates for the synthesis are the products resulting from the addition of suitable organolithium. compounds to either Garner's aldehyde or its enantiomer. The final products are obtained by TMSTf-induced cleavage of the protecting groups and N-acylation, both under specific conditions. An alternative method for N-Boc deprotection is also reported that allows us to obtain the cyclopropene analogue of sphingosine 12a, which can be transformed into GT11 upon acylation. The procedure consists of the conversion of the Garner aldehyde addition products into the bicyclic dihydrooxazolo[3,4,0]oxazol-3-ones 19 by transesterification in basic medium of the tert-butyl group with the hydroxyl function at C3. Mild cleavage of the N,O-isopropylidene cyclic acetal present in 19 affords the oxazolidin-2-one 20, which gives 12a upon saponification. Furthermore, compound 20 is also the key intermediate in the synthesis of the terminal deoxy, methoxy, and fluoro derivatives 9, 10, and 11, respectively. Determination of dihydroceramide desaturase activity in vitro showed that GT11 was a competitive inhibitor (K-i = 6 muM) and that its analogues with N-hexanoyl (6) and N-decanoyl (7) moieties inhibited the enzyme with similar potencies (IC50 = 13 and 31 muM, respectively). No decrease in dihydroceramide desaturase activity was observed with any of the other compounds tested.

  DOI：

  10.1021/jo030141u

文献信息

• Synthesis of a Cyclopropene Analogue of Ceramide, a Potent Inhibitor of Dihydroceramide Desaturase
  作者：Gemma Triola、Gemma Fabriàs、Amadeu Llebaria

  DOI：10.1002/1521-3773(20010518)40:10<1960::aid-anie1960>3.0.co;2-v

  日期：2001.5.18
• Analogs of the dihydroceramide desaturase inhibitor GT11 modified at the amide function: synthesis and biological activities
  作者：Carmen Bedia、Gemma Triola、Josefina Casas、Amadeu Llebaria、Gemma Fabriàs

  DOI：10.1039/b510198k

  日期：——

  Dihydroceramide desaturase is the last enzyme in the biosynthesis of ceramide de novo. The cyclopropene-containing sphingolipid GT11 is a competitive inhibitor of dihydroceramide desaturase. The biological effects of chemical modification of the GT11 amide linkage are reported in this article. Either N-methyl substitution or replacement of the amide α-carbonyl methylene by oxygen result in inactive compounds. In contrast, both urea (3) and thiourea (4) analogs of GT11, as well as three α-ketoamides (5–7), did inhibit the desaturation of N-octanoylsphinganine to N-octanoylsphingosine, although with significantly lower potency than GT11. Furthermore, the α-ketoamides 5–7 inhibit the acidic ceramidase with similar potencies (IC50 52–83 µM). Inhibition of the neutral/alkaline ceramidase by these compounds requires around 20-fold higher concentrations. Structure–activity relationships and the biological interest of these compounds are discussed.

  二氢酰胺去饱和酶是神经酰胺新合成中的最后一个酶。含环丙烯的鞘脂GT11是二氢酰胺去饱和酶的竞争性抑制剂。本文报告了对GT11酰胺键的化学修饰的生物学效应。N-甲基取代或将酰胺α-羰基亚甲基替换为氧会导致化合物失活。相比之下，GT11的脲化合物（3）和硫脲化合物（4）以及三种α-酮酰胺（5–7）确实抑制了N-辛酰鞘氨醇向N-辛酰神经酰胺的去饱和，尽管其效力显著低于GT11。此外，α-酮酰胺5–7也以相似的效力抑制酸性神经酰胺酶（IC50 52–83 µM）。这些化合物对中性/碱性神经酰胺酶的抑制需要约20倍的更高浓度。文中讨论了这些化合物的结构-活性关系和生物学兴趣。
• Synthesis of Cyclopropene Analogues of Ceramide and Their Effect on Dihydroceramide Desaturase
  作者：Gemma Triola、Gemma Fabriàs、Josefina Casas、Amadeu Llebaria

  DOI：10.1021/jo030141u

  日期：2003.12.1

  The synthesis of several analogues of the N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first reported inhibitor of dihydroceramide desaturase, as well as their effects on this enzyme, are described. Modifications of the parent structure include variations on the cyclopropene ring, the N-acyl chain length, the configuration of the stereocenters, and the hydroxyl group at C1. The key intermediates for the synthesis are the products resulting from the addition of suitable organolithium. compounds to either Garner's aldehyde or its enantiomer. The final products are obtained by TMSTf-induced cleavage of the protecting groups and N-acylation, both under specific conditions. An alternative method for N-Boc deprotection is also reported that allows us to obtain the cyclopropene analogue of sphingosine 12a, which can be transformed into GT11 upon acylation. The procedure consists of the conversion of the Garner aldehyde addition products into the bicyclic dihydrooxazolo[3,4,0]oxazol-3-ones 19 by transesterification in basic medium of the tert-butyl group with the hydroxyl function at C3. Mild cleavage of the N,O-isopropylidene cyclic acetal present in 19 affords the oxazolidin-2-one 20, which gives 12a upon saponification. Furthermore, compound 20 is also the key intermediate in the synthesis of the terminal deoxy, methoxy, and fluoro derivatives 9, 10, and 11, respectively. Determination of dihydroceramide desaturase activity in vitro showed that GT11 was a competitive inhibitor (K-i = 6 muM) and that its analogues with N-hexanoyl (6) and N-decanoyl (7) moieties inhibited the enzyme with similar potencies (IC50 = 13 and 31 muM, respectively). No decrease in dihydroceramide desaturase activity was observed with any of the other compounds tested.