(2,6-di-O-acetyl-β-D-galactopyranosyl)-(1->3)-4-O-acetyl-1,5-anhydro-6-O-(biphenyl-4-yl-methyl)-2-deoxy-D-lyxo-hexitol | 1123178-86-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2,6-di-O-acetyl-β-D-galactopyranosyl)-(1->3)-4-O-acetyl-1,5-anhydro-6-O-(biphenyl-4-yl-methyl)-2-deoxy-D-lyxo-hexitol
• 英文别名: [(2R,3R,4S,5R,6R)-5-acetyloxy-6-[(2R,3R,4R)-3-acetyloxy-2-[(4-phenylphenyl)methoxymethyl]oxan-4-yl]oxy-3,4-dihydroxyoxan-2-yl]methyl acetate
• CAS: 1123178-86-8
• 化学式: C₃₁H₃₈O₁₂
• 分子量: 602.636
• InChiKey: PZPDZTILYNYGPM-YZYLEJJVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  43
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  156
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  methyl (methyl 5-acetamido-4,7,8-tri-O-acetyl-9-azido-2-thio-3,5,9-trideoxy-D-glycero-D-galacto-2-nonulopyranosid)onate 、 (2,6-di-O-acetyl-β-D-galactopyranosyl)-(1->3)-4-O-acetyl-1,5-anhydro-6-O-(biphenyl-4-yl-methyl)-2-deoxy-D-lyxo-hexitol 在 N-碘代丁二酰亚胺 、 三氟甲磺酸 作用下， 以 乙腈 为溶剂， 以61%的产率得到(methyl 5-acetamido-4,7,8-tri-O-acetyl-9-azido-3,5,9-trideoxy-D-glycero-α-D-galacto-2-nonulopyranosynate)-(2->3)-(2,6-Di-O-acetyl-β-D-galactopyranosyl)-(1->3)-4-O-acetyl-1,5-anhydro-6-O-(biphenyl-4-yl-methyl)-2-deoxy-D-lyxo-hexitol
  参考文献：
  名称：

  From the Ganglioside GQ1b? to Glycomimetic Antagonists of the Myelin-Associated Glycoprotein (MAG)

  摘要：

  四糖4，是神经节苷脂GQ1b的亚结构，对髓鞘相关糖蛋白（MAG）具有显著的亲和力，因此被选为引导优化计划的起点。在寻找结构简化和药代动力学改进的4的类似物时，对核心二糖Gal?(1-3)GalNAc以及末端?(2-3)-和内部?(2-6)-连接的神经酸进行了修饰，并在基于靶点的结合测定中进行了合成和测试。与参考四糖4相比，最有效的拮抗剂17表现出360倍的亲和力改进。此外，药代动力学参数，如在脑脊液中的稳定性，logD值和通过血脑屏障的渗透性，表明拮抗剂17具有类似药物的特性。

  DOI：

  10.2533/chimia.2010.17
• 作为产物：
  描述：

  (2,6-di-O-acetyl-3,4-O-isopropylidene-β-D-galactopyranosyl)-(1->3)-4-O-acetyl-1,5-anhydro-6-O-(biphenyl-4-ylmethyl)-2-deoxy-D-lyxo-hexitol 在 水 、 溶剂黄146 作用下， 反应 2.5h， 以81%的产率得到(2,6-di-O-acetyl-β-D-galactopyranosyl)-(1->3)-4-O-acetyl-1,5-anhydro-6-O-(biphenyl-4-yl-methyl)-2-deoxy-D-lyxo-hexitol
  参考文献：
  名称：

  Examination of the Biological Role of the α(2→6)-Linked Sialic Acid in Gangliosides Binding to the Myelin-Associated Glycoprotein (MAG)

  摘要：

  The tetrasaccharide 1, a substructure of ganglioside GQ1b alpha, shows a remarkable affinity for the myelin-associated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 1, modifications of the core disaccharide, the alpha(2 -> 3)- and the alpha(2 -> 6)-linked sialic acid were synthesized. Biphenylmethyl and (S)-lactate were identified as suitable replacements for the alpha(2 -> 6)-linked sialic acid. Combined with a core modification and the earlier found aryl amide substituent in the 9-position of the alpha(2 -> 3)-linked sialic acid, high affinity MAG antagonists were identified. All mimics were tested in a competitive target-based binding assay, providing relative inhibitory potencies (rlP). Compared to the reference tetrasaccharide 1, the rIPs of the most potent antagonists 59 and 60 are enhanced nearly 400-fold. Their K(D)s determined in surface plasmon resonance experiments are in the low micromolar range. These results are in semiquantitative agreement with molecular modeling studies. This new class of glycomimetics will allow to validate the role of MAG in the axon regeneration process.

  DOI：

  10.1021/jm801058n

文献信息

• From the Ganglioside GQ1b? to Glycomimetic Antagonists of the Myelin-Associated Glycoprotein (MAG)
  作者：Beat Ernst、Oliver Schwardt、Stefanie Mesch、Matthias Wittwer、Gianluca Rossato、Angelo Vedani

  DOI：10.2533/chimia.2010.17

  日期：——

  The tetrasaccharide 4, a substructure of ganglioside GQ1b?, shows a remarkable affinity for the myelin-associated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 4, antagonists with modifications of the core disaccharide Gal?(1-3)GalNAc, as well as the terminal ?(2-3)- and the internal ?(2-6)-linked neuraminic acid were synthesized and tested in target-based binding assays. Compared to the reference tetrasaccharide 4, the most potent antagonist 17 exhibits a 360-fold improved affinity. Furthermore, pharmacokinetic parameters such as stability in the cerebrospinal fluid, logD and permeation through the BBB indicate the drug-like properties of antagonist 17.

  四糖4，是神经节苷脂GQ1b的亚结构，对髓鞘相关糖蛋白（MAG）具有显著的亲和力，因此被选为引导优化计划的起点。在寻找结构简化和药代动力学改进的4的类似物时，对核心二糖Gal?(1-3)GalNAc以及末端?(2-3)-和内部?(2-6)-连接的神经酸进行了修饰，并在基于靶点的结合测定中进行了合成和测试。与参考四糖4相比，最有效的拮抗剂17表现出360倍的亲和力改进。此外，药代动力学参数，如在脑脊液中的稳定性，logD值和通过血脑屏障的渗透性，表明拮抗剂17具有类似药物的特性。
• Examination of the Biological Role of the α(2→6)-Linked Sialic Acid in Gangliosides Binding to the Myelin-Associated Glycoprotein (MAG)
  作者：Oliver Schwardt、Heiko Gäthje、Angelo Vedani、Stefanie Mesch、Gan-Pan Gao、Morena Spreafico、Johannes von Orelli、Sørge Kelm、Beat Ernst

  DOI：10.1021/jm801058n

  日期：2009.2.26

  The tetrasaccharide 1, a substructure of ganglioside GQ1b alpha, shows a remarkable affinity for the myelin-associated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 1, modifications of the core disaccharide, the alpha(2 -> 3)- and the alpha(2 -> 6)-linked sialic acid were synthesized. Biphenylmethyl and (S)-lactate were identified as suitable replacements for the alpha(2 -> 6)-linked sialic acid. Combined with a core modification and the earlier found aryl amide substituent in the 9-position of the alpha(2 -> 3)-linked sialic acid, high affinity MAG antagonists were identified. All mimics were tested in a competitive target-based binding assay, providing relative inhibitory potencies (rlP). Compared to the reference tetrasaccharide 1, the rIPs of the most potent antagonists 59 and 60 are enhanced nearly 400-fold. Their K(D)s determined in surface plasmon resonance experiments are in the low micromolar range. These results are in semiquantitative agreement with molecular modeling studies. This new class of glycomimetics will allow to validate the role of MAG in the axon regeneration process.