benzyl 3,5,9-trideoxy-5-glycolamido-9-(4'-hydroxy-4-biphenyl)acetamido-D-glycero-α-D-galacto-2-nonulopyranosidonic acid | 1195053-37-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: benzyl 3,5,9-trideoxy-5-glycolamido-9-(4'-hydroxy-4-biphenyl)acetamido-D-glycero-α-D-galacto-2-nonulopyranosidonic acid
• 英文别名: (2R,4S,5R,6R)-6-[(1R,2R)-1,2-dihydroxy-3-[[2-[4-(4-hydroxyphenyl)phenyl]acetyl]amino]propyl]-4-hydroxy-5-[(2-hydroxyacetyl)amino]-2-phenylmethoxyoxane-2-carboxylic acid
• CAS: 1195053-37-2
• 化学式: C₃₂H₃₆N₂O₁₁
• 分子量: 624.645
• InChiKey: OYVPUTMZTUBFKJ-OVRIQYAISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  45
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  215
• 氢给体数：
  8
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  4'-hydroxybiphenyl-4-acetic acid NHS ester 、 benzyl 9-amino-3,5,9-trideoxy-5-glycolamido-D-glycero-α-D-galacto-2-nonulopyranosidonic acid 在 碳酸氢钠 作用下， 以 水 、 乙腈 为溶剂， 生成 benzyl 3,5,9-trideoxy-5-glycolamido-9-(4'-hydroxy-4-biphenyl)acetamido-D-glycero-α-D-galacto-2-nonulopyranosidonic acid
  参考文献：
  名称：

  CD22-Antagonists with nanomolar potency: The synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold

  摘要：

  In earlier studies, we identified the C-9 amido derivative 1 (9-(4'-hydroxy-4-biphenyl)acetamido-9-deoxy-Neu5Gc alpha 2-6GalOMP) and the C-9 amino derivative 2 (9-(4'-hydroxy-4-biphenyl)methylamino-9-deoxy-Neu5Gc alpha 2-6GalOMP) have the most promising affinity for mouse CD22 and human CD22, respectively. Replacing the subterminal galactose residue (2-6Gal-OMP) of 1 with benzyl (5) or biphenylmethyl (6) as aglycone led to even higher potency for mCD22. In this study, both compounds showed improved potency and selectivity for CD22 (IC(50) 70 nM) and 712-fold more selective for CD22 than for MAG. The corresponding derivatives of 2, compounds 8 and 9, showed comparable activity to 2 but lower potency and selectivity than 5 and 6. Although compounds 5-9 are simple and small molecular weight antagonists, they showed much high potency and selectivity than the corresponding compounds having a 2-6Gal linkage. Both biological and computational docking simulation studies suggest that the 2-6GalOMP residues of 1 and 2 are not critical for binding process and could be replaced with hydrophobic non-carbohydrate moieties. The data presented herein has significant implications for the design and discovery of next-generation CD22-antagonists. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.01.060

文献信息

• Potent small molecule mouse CD22-inhibitors: Exploring the interaction of the residue at C-2 of sialic acid scaffold
  作者：Hajjaj H.M. Abdu-Allah、Kozo Watanabe、Koji Hayashizaki、Chiaki Takaku、Taichi Tamanaka、Hiromu Takematsu、Yasunori Kozutsumi、Takeshi Tsubata、Hideharu Ishida、Makoto Kiso

  DOI：10.1016/j.bmcl.2009.08.044

  日期：2009.10

  Our previous study revealed that compound 1 (9-(4'-hydroxy-4-biphenyl)acetamido-9-deoxy-Neu5Gc alpha 2-6GalOMP) has the most promising affinity for mCD22. Replacing the subterminal galactose residue of 1 with benzyl or biphenylmethyl as aglycone led to 38- and 20-fold higher potency, respectively. This discovery represents a new direction in inhibitor design suitable for pharmaceutical development. (C) 2009 Elsevier Ltd. All rights reserved.
• CD22-Antagonists with nanomolar potency: The synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold
  作者：Hajjaj H.M. Abdu-Allah、Kozo Watanabe、Gladys C. Completo、Magesh Sadagopan、Koji Hayashizaki、Chiaki Takaku、Taichi Tamanaka、Hiromu Takematsu、Yasunori Kozutsumi、James C. Paulson、Takeshi Tsubata、Hiromune Ando、Hideharu Ishida、Makoto Kiso

  DOI：10.1016/j.bmc.2011.01.060

  日期：2011.3

  In earlier studies, we identified the C-9 amido derivative 1 (9-(4'-hydroxy-4-biphenyl)acetamido-9-deoxy-Neu5Gc alpha 2-6GalOMP) and the C-9 amino derivative 2 (9-(4'-hydroxy-4-biphenyl)methylamino-9-deoxy-Neu5Gc alpha 2-6GalOMP) have the most promising affinity for mouse CD22 and human CD22, respectively. Replacing the subterminal galactose residue (2-6Gal-OMP) of 1 with benzyl (5) or biphenylmethyl (6) as aglycone led to even higher potency for mCD22. In this study, both compounds showed improved potency and selectivity for CD22 (IC(50) 70 nM) and 712-fold more selective for CD22 than for MAG. The corresponding derivatives of 2, compounds 8 and 9, showed comparable activity to 2 but lower potency and selectivity than 5 and 6. Although compounds 5-9 are simple and small molecular weight antagonists, they showed much high potency and selectivity than the corresponding compounds having a 2-6Gal linkage. Both biological and computational docking simulation studies suggest that the 2-6GalOMP residues of 1 and 2 are not critical for binding process and could be replaced with hydrophobic non-carbohydrate moieties. The data presented herein has significant implications for the design and discovery of next-generation CD22-antagonists. (C) 2011 Elsevier Ltd. All rights reserved.