(2S,5R)-5-(6-amino-2-((4-(3-((4-hydroxy-3-nitrophenyl)amino)-3-oxopropyl)phenethyl)amino)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: (2S,5R)-5-(6-amino-2-((4-(3-((4-hydroxy-3-nitrophenyl)amino)-3-oxopropyl)phenethyl)amino)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide
• 英文别名: (2S,3S,4R,5R)-5-[6-amino-2-[2-[4-[3-(4-hydroxy-3-nitroanilino)-3-oxopropyl]phenyl]ethylamino]purin-9-yl]-N-ethyl-3,4-dihydroxyoxolane-2-carboxamide
• 化学式: C₂₉H₃₃N₉O₈
• 分子量: 635.637
• InChiKey: UXTWNGBPJFUVIK-NLJXWPIHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  46
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  256
• 氢给体数：
  7
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  (2S,5R)-5-(6-amino-2-((4-(3-((4-hydroxy-3-nitrophenyl)amino)-3-oxopropyl)phenethyl)amino)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide 、 D-生物素 在 4-二甲氨基吡啶 、 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， 以50%的产率得到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
• 作为产物：
  描述：

  2-硝基-4-氨基苯酚 、 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 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以60%的产率得到(2S,5R)-5-(6-amino-2-((4-(3-((4-hydroxy-3-nitrophenyl)amino)-3-oxopropyl)phenethyl)amino)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide
  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.