(2-acetamido-2-deoxy-α-D-glucopyranosyloxycarbonyl)propylamine | 1135137-21-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2-acetamido-2-deoxy-α-D-glucopyranosyloxycarbonyl)propylamine
• 英文别名: 2-(Acetylamino)-2-Deoxy-1-O-(Propylcarbamoyl)-Alpha-D-Glucopyranose；[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl] N-propylcarbamate
• CAS: 1135137-21-1
• 化学式: C₁₂H₂₂N₂O₇
• 分子量: 306.316
• InChiKey: WEAGJSCGQDTQRE-ISUQUUIWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  137
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyloxycarbonyl)-propylamine 在 甲醇 、 二甲基十二/十四烷基叔胺 作用下， 反应 72.0h， 以100%的产率得到(2-acetamido-2-deoxy-α-D-glucopyranosyloxycarbonyl)propylamine
  参考文献：
  名称：

  Structural Basis of Multivalent Binding to Wheat Germ Agglutinin

  摘要：

  The inhibition of carbohydrate protein interactions by tailored multivalent ligands is a powerful strategy for the treatment of many human diseases. Crucial for the success of this approach is an understanding of the molecular mechanisms as to how a binding enhancement of a multivalent ligand is achieved. We have synthesized a series of multivalent N-acetylglucosamine (GIcNAc) derivatives and studied their interaction with the plant lectin wheat germ agglutinin (WGA) by an enzyme-linked lectin assay (ELLA) and X-ray crystallography. The solution conformation of one ligand was determined by NMR spectroscopy. Employing a GIcNAc carbamate motif with alpha-configuration and by systematic variation of the spacer length, we were able to identify divalent ligands with unprecedented high WGA binding potency. The best divalent ligand has an IC(50) value of 9.8 mu M (ELLA) corresponding to a relative potency of 2350 (1170 on a valency-corrected basis, i.e., per mol sugar contained) compared to free GIcNAc. X-ray crystallography of the complex of WGA and the second best, closely related divalent ligand explains this activity. Four divalent molecules simultaneously bind to WGA with each ligand bridging adjacent binding sites. This shows for the first time that all eight sugar binding sites of the WGA dimer are simultaneously functional. We also report a tetravalent neoglycopeptide with an IC(50) value of 0.9 mu M being 25 500 times higher than that of GIcNAc (6400 times per contained sugar) and the X-ray structure analysis of its complex with glutaraldehyde-cross-linked WGA. Comparison of the crystal structure and the solution NMR structure of the neoglycopeptide as well as results from the ELLA suggest that the conformation of the glycopeptide in solution is already preorganized in a way supporting multivalent binding to the protein. Our findings show that bridging adjacent protein binding sites by multivalent ligands is a valid strategy to find high-affinity protein ligands and that even subtle changes of the linker structure can have a significant impact on the binding affinity.

  DOI：

  10.1021/ja101646k

文献信息

• Structural Basis of Multivalent Binding to Wheat Germ Agglutinin
  作者：David Schwefel、Caroline Maierhofer、Johannes G. Beck、Sonja Seeberger、Kay Diederichs、Heiko M. Möller、Wolfram Welte、Valentin Wittmann

  DOI：10.1021/ja101646k

  日期：2010.6.30

  The inhibition of carbohydrate protein interactions by tailored multivalent ligands is a powerful strategy for the treatment of many human diseases. Crucial for the success of this approach is an understanding of the molecular mechanisms as to how a binding enhancement of a multivalent ligand is achieved. We have synthesized a series of multivalent N-acetylglucosamine (GIcNAc) derivatives and studied their interaction with the plant lectin wheat germ agglutinin (WGA) by an enzyme-linked lectin assay (ELLA) and X-ray crystallography. The solution conformation of one ligand was determined by NMR spectroscopy. Employing a GIcNAc carbamate motif with alpha-configuration and by systematic variation of the spacer length, we were able to identify divalent ligands with unprecedented high WGA binding potency. The best divalent ligand has an IC(50) value of 9.8 mu M (ELLA) corresponding to a relative potency of 2350 (1170 on a valency-corrected basis, i.e., per mol sugar contained) compared to free GIcNAc. X-ray crystallography of the complex of WGA and the second best, closely related divalent ligand explains this activity. Four divalent molecules simultaneously bind to WGA with each ligand bridging adjacent binding sites. This shows for the first time that all eight sugar binding sites of the WGA dimer are simultaneously functional. We also report a tetravalent neoglycopeptide with an IC(50) value of 0.9 mu M being 25 500 times higher than that of GIcNAc (6400 times per contained sugar) and the X-ray structure analysis of its complex with glutaraldehyde-cross-linked WGA. Comparison of the crystal structure and the solution NMR structure of the neoglycopeptide as well as results from the ELLA suggest that the conformation of the glycopeptide in solution is already preorganized in a way supporting multivalent binding to the protein. Our findings show that bridging adjacent protein binding sites by multivalent ligands is a valid strategy to find high-affinity protein ligands and that even subtle changes of the linker structure can have a significant impact on the binding affinity.