4-(3-(4-(2-((6-amino-9-((2R,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)amino)ethyl)phenyl)propanamido)-2-nitrophenyl 5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 生物素及其衍生物
• 英文名称: 4-(3-(4-(2-((6-amino-9-((2R,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)amino)ethyl)phenyl)propanamido)-2-nitrophenyl 5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate
• 英文别名: [4-[3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxyoxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoylamino]-2-nitrophenyl] 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoate
• 化学式: C₃₉H₄₇N₁₁O₁₀S
• 分子量: 861.936
• InChiKey: MUXUIVVLQXFMRX-CXJTVLAKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  61
• 可旋转键数：
  18
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  328
• 氢给体数：
  8
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  4-[2-[[6-氨基-9-(N-乙基-BETA-D-呋喃核糖酰胺基)-9H-嘌呤-2-基]氨基]乙基]苯丙酸 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 4-(3-(4-(2-((6-amino-9-((2R,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)amino)ethyl)phenyl)propanamido)-2-nitrophenyl 5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate
  参考文献：
  名称：

  Structure-Based Design of Reactive Nucleosides for Site-Specific Modification of the A_2A Adenosine Receptor

  摘要：

  Adenosine receptors (ARs) are members of the G protein-coupled receptor (GPCR) superfamily and have shown much promise as therapeutic targets. We have used an agonist-bound A2AAR X-ray crystallographic structure to design a chemically reactive agonist for site-specific chemical modification of the receptor. To further explore and chemically engineer its binding cavity, a 2-nitrophenyl active ester was attached through an elongated chain at adenine C2 position. This general structure was designed for irreversible transfer of a terminal acyl group to a nucleophilic amino group on the A2AAR. Preincubation with several O-acyl derivatives prevented radioligand binding that was not regenerated upon extensive washing. In silico receptor docking suggested two lysine residues (second extracellular loop) as potential target sites for an O-acetyl derivative (MRS5854, 3a), and site-directed mutagenesis indicated that K153 but not K150 is essential. Similarly, a butyl azide for click reaction was incorporated in the active ester moiety (3b). These promising results indicate a stable, covalent modification of the receptor by several reactive adenosine derivatives, which could be chemical tools for future imaging, structural probing, and drug discovery. Thus, structure-based ligand design has guided the site-specific modification of a GPCR.

  DOI：

  10.1021/ml5002486

文献信息

• Structure-Based Design of Reactive Nucleosides for Site-Specific Modification of the A_2A Adenosine Receptor
  作者：Steven M. Moss、P. Suresh Jayasekara、Silvia Paoletta、Zhan-Guo Gao、Kenneth A. Jacobson

  DOI：10.1021/ml5002486

  日期：2014.9.11

  Adenosine receptors (ARs) are members of the G protein-coupled receptor (GPCR) superfamily and have shown much promise as therapeutic targets. We have used an agonist-bound A2AAR X-ray crystallographic structure to design a chemically reactive agonist for site-specific chemical modification of the receptor. To further explore and chemically engineer its binding cavity, a 2-nitrophenyl active ester was attached through an elongated chain at adenine C2 position. This general structure was designed for irreversible transfer of a terminal acyl group to a nucleophilic amino group on the A2AAR. Preincubation with several O-acyl derivatives prevented radioligand binding that was not regenerated upon extensive washing. In silico receptor docking suggested two lysine residues (second extracellular loop) as potential target sites for an O-acetyl derivative (MRS5854, 3a), and site-directed mutagenesis indicated that K153 but not K150 is essential. Similarly, a butyl azide for click reaction was incorporated in the active ester moiety (3b). These promising results indicate a stable, covalent modification of the receptor by several reactive adenosine derivatives, which could be chemical tools for future imaging, structural probing, and drug discovery. Thus, structure-based ligand design has guided the site-specific modification of a GPCR.