2-amino-N-(2-((2-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)ethyl)amino)-2-oxoethyl)-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxamide | 1387563-75-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 5'-脱氧核糖核苷
• 英文名称: 2-amino-N-(2-((2-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)ethyl)amino)-2-oxoethyl)-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxamide
• 英文别名: 2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxylic acid (2-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethanesulfonyl]-ethylcarbamoyl)-methylamide；5'-{[2-({n-[(2-Amino-7,7-Dimethyl-4-Oxo-3,4,7,8-Tetrahydropteridin-6-Yl)carbonyl]glycyl}amino)ethyl]sulfonyl}-5'-Deoxyadenosine；2-amino-N-[2-[2-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfonyl]ethylamino]-2-oxoethyl]-7,7-dimethyl-4-oxo-3,8-dihydropteridine-6-carboxamide
• CAS: 1387563-75-8
• 化学式: C₂₃H₃₀N₁₂O₈S
• 分子量: 634.633
• InChiKey: QCWCABDSXQYDST-GWKRVTOESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.6
• 重原子数：
  44
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  312
• 氢给体数：
  8
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  5'-O-(苄基磺酰基)-2',3'-O-异亚丙基腺苷 在 oxone 、 sodium methylate 、 potassium carbonate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.25h， 生成 2-amino-N-(2-((2-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl)ethyl)amino)-2-oxoethyl)-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxamide
  参考文献：
  名称：

  Bisubstrate analog inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New lead exhibits a distinct binding mode

  摘要：

  6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthesis pathway catalyzing the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin, is an attractive target for developing novel antimicrobial agents. Previously, we studied the mechanism of HPPK action, synthesized bisubstrate analog inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed a new generation of bisubstrate inhibitors by replacing the phosphate bridge with a piperidine-containing linkage. To further improve linker properties, we have synthesized a new compound, characterized its protein binding/inhibiting properties, and determined its structure in complex with HPPK. Surprisingly, this inhibitor exhibits a new binding mode in that the adenine base is flipped when compared to previously reported structures. Furthermore, the side chain of amino acid residue E77 is involved in protein-inhibitor interaction, forming hydrogen bonds with both 2' and 3' hydroxyl groups of the ribose moiety. Residue E77 is conserved among HPPK sequences, but interacts only indirectly with the bound MgATP via water molecules. Never observed before, the E77-ribose interaction is compatible only with the new inhibitor-binding mode. Therefore, this compound represents a new direction for further development. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2012.05.060

文献信息

• Bisubstrate analog inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New lead exhibits a distinct binding mode
  作者：Genbin Shi、Gary Shaw、Yue Li、Yan Wu、Honggao Yan、Xinhua Ji

  DOI：10.1016/j.bmc.2012.05.060

  日期：2012.7

  6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthesis pathway catalyzing the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin, is an attractive target for developing novel antimicrobial agents. Previously, we studied the mechanism of HPPK action, synthesized bisubstrate analog inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed a new generation of bisubstrate inhibitors by replacing the phosphate bridge with a piperidine-containing linkage. To further improve linker properties, we have synthesized a new compound, characterized its protein binding/inhibiting properties, and determined its structure in complex with HPPK. Surprisingly, this inhibitor exhibits a new binding mode in that the adenine base is flipped when compared to previously reported structures. Furthermore, the side chain of amino acid residue E77 is involved in protein-inhibitor interaction, forming hydrogen bonds with both 2' and 3' hydroxyl groups of the ribose moiety. Residue E77 is conserved among HPPK sequences, but interacts only indirectly with the bound MgATP via water molecules. Never observed before, the E77-ribose interaction is compatible only with the new inhibitor-binding mode. Therefore, this compound represents a new direction for further development. Published by Elsevier Ltd.