(3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylacetylphosphonic acid | 1452388-43-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylacetylphosphonic acid
• 英文别名: [2-[(3R,4S)-3-(2-amino-6-oxo-1H-purin-9-yl)-4-hydroxypyrrolidin-1-yl]-2-oxoethyl]phosphonic acid
• CAS: 1452388-43-0
• 化学式: C₁₁H₁₅N₆O₆P
• 分子量: 358.25
• InChiKey: PIHCTBQWWHFPNB-RITPCOANSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  183
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidine 在 4-二甲氨基吡啶 、 三甲基溴硅烷 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylacetylphosphonic acid
  参考文献：
  名称：

  Inhibition of the Escherichia coli 6-Oxopurine Phosphoribosyltransferases by Nucleoside Phosphonates: Potential for New Antibacterial Agents

  摘要：

  Escherichia coli (Ec) cells possess two purine salvage enzymes: xanthine-guanine phosphoribosyltransferase (XGPRT) and hypoxanthine phosphoribosyltransferase (HPRT). EcXGPRT shares a common structural feature with other members of this family, a flexible loop that closes over the active site during catalysis. The replacement of six of these amino acids by alanine has no effect on the K-m for the two substrates. However; the K-i for the nucleoside monophosphate increases by 27-fold, and the k(cat) is reduced by similar to 200-fold. Nucleoside. phosphonates (NP) are good inhibitors of EcXGPRT and EcHPRT, with K-i values as low as 10 nM. In the absence of the flexible loop, these values increase by 5- to 30-fold, indicating the importance of the loop for high-affinity inhibition. Crystal structures of two NPs in complex with EcXGPRT explain the tight binding. Prodrugs of NPs with low K-i values for EcXGPRT or EcHPRT exhibit IC50 values between 5 and 23 mu M against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria.

  DOI：

  10.1021/jm400779n

文献信息

• Inhibition of the <i>Escherichia coli</i> 6-Oxopurine Phosphoribosyltransferases by Nucleoside Phosphonates: Potential for New Antibacterial Agents
  作者：Dianne T. Keough、Dana Hocková、Dominik Rejman、Petr Špaček、Silvie Vrbková、Marcela Krečmerová、Wai Soon Eng、Harmen Jans、Nicholas P. West、Lieve M. J. Naesens、John de Jersey、Luke W. Guddat

  DOI：10.1021/jm400779n

  日期：2013.9.12

  Escherichia coli (Ec) cells possess two purine salvage enzymes: xanthine-guanine phosphoribosyltransferase (XGPRT) and hypoxanthine phosphoribosyltransferase (HPRT). EcXGPRT shares a common structural feature with other members of this family, a flexible loop that closes over the active site during catalysis. The replacement of six of these amino acids by alanine has no effect on the K-m for the two substrates. However; the K-i for the nucleoside monophosphate increases by 27-fold, and the k(cat) is reduced by similar to 200-fold. Nucleoside. phosphonates (NP) are good inhibitors of EcXGPRT and EcHPRT, with K-i values as low as 10 nM. In the absence of the flexible loop, these values increase by 5- to 30-fold, indicating the importance of the loop for high-affinity inhibition. Crystal structures of two NPs in complex with EcXGPRT explain the tight binding. Prodrugs of NPs with low K-i values for EcXGPRT or EcHPRT exhibit IC50 values between 5 and 23 mu M against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria.