9-[(N-(3-cyanopropyl)-N-(2-phosphonoethyl))-2-aminoethyl]hypoxanthine | 1383382-01-1

• 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: 9-[(N-(3-cyanopropyl)-N-(2-phosphonoethyl))-2-aminoethyl]hypoxanthine
• 英文别名: 9-[(N-(2-cyanopropyl)-N-(2-phosphonoethyl))-2-aminoethyl]hypoxanthine；2-[3-cyanopropyl-[2-(6-oxo-1H-purin-9-yl)ethyl]amino]ethylphosphonic acid
• CAS: 1383382-01-1
• 化学式: C₁₃H₁₉N₆O₄P
• 分子量: 354.305
• InChiKey: KKGWUKXRRUKRLT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.6
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  144
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  9-[(N-(3-cyanopropyl)-N-(2-diethoxyphosphorylethyl))-2-aminoethyl]hypoxanthine 在 2,6-二甲基吡啶 、 三甲基溴硅烷 作用下， 以 乙腈 为溶剂， 反应 48.0h， 以51%的产率得到9-[(N-(3-cyanopropyl)-N-(2-phosphonoethyl))-2-aminoethyl]hypoxanthine
  参考文献：
  名称：

  Synthesis of Novel N-Branched Acyclic Nucleoside Phosphonates As Potent and Selective Inhibitors of Human, Plasmodium falciparum and Plasmodium vivax 6-Oxopurine Phosphoribosyltransferases

  摘要：

  Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) is crucial for the survival of malarial parasites Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). Acyclic nucleoside phosphonates (ANPs) are inhibitors of HG(X)PRT and arrest the growth of Pf in cell culture. Here, a novel class of ANPs containing trisubstituted nitrogen (aza-ANPs) has been synthesized. These compounds have a wide range of K-i values and selectivity for human HGPRT, PfHGXPRT, and PvHGPRT. The most selective and potent inhibitor of PfHGXPRT is 9-N-(3-methoxy-3-oxopropyl)-N-(2-phosphonoethyl)-2-aminoethyl]hypoxanthine (K-i = 100 nM): no inhibition could be detected against the human enzyme. This compound exhibits the highest ever reported selectivity for PfHGXPRT compared to human HGPRT. For PvHGPRT, 9-[N-(2-carboxyethyl)-N-(2-phosphonoethyl)-2-aminoethyl]guanine has a Ki of SO nM, the best inhibitor discovered for this enzyme to date. Docking of these compounds into the known structures of human HGPRT in complex with ANP-based inhibitors suggests reasons for the variations in affinity, providing insights for the design of antimalarial drug candidates.

  DOI：

  10.1021/jm300662d

文献信息

• [EN] 6-OXOPURINE PHOSPHORIBOSYLTRANSFERASE INHIBITORS<br/>[FR] INHIBITEURS DE 6-OXOPURINE PHOSPHORIBOSYLTRANSFÉRASE
  申请人：UNIV QUEENSLAND

  公开号：WO2013166545A3

  公开（公告）日：2015-03-05
• EP2847201B1
  申请人：——

  公开号：EP2847201B1

  公开（公告）日：2017-08-16
• Synthesis of Novel <i>N</i>-Branched Acyclic Nucleoside Phosphonates As Potent and Selective Inhibitors of Human, Plasmodium falciparum and Plasmodium vivax 6-Oxopurine Phosphoribosyltransferases
  作者：Dana Hocková、Dianne T. Keough、Zlatko Janeba、Tzu-Hsuan Wang、John de Jersey、Luke W. Guddat

  DOI：10.1021/jm300662d

  日期：2012.7.12

  Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) is crucial for the survival of malarial parasites Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). Acyclic nucleoside phosphonates (ANPs) are inhibitors of HG(X)PRT and arrest the growth of Pf in cell culture. Here, a novel class of ANPs containing trisubstituted nitrogen (aza-ANPs) has been synthesized. These compounds have a wide range of K-i values and selectivity for human HGPRT, PfHGXPRT, and PvHGPRT. The most selective and potent inhibitor of PfHGXPRT is 9-N-(3-methoxy-3-oxopropyl)-N-(2-phosphonoethyl)-2-aminoethyl]hypoxanthine (K-i = 100 nM): no inhibition could be detected against the human enzyme. This compound exhibits the highest ever reported selectivity for PfHGXPRT compared to human HGPRT. For PvHGPRT, 9-[N-(2-carboxyethyl)-N-(2-phosphonoethyl)-2-aminoethyl]guanine has a Ki of SO nM, the best inhibitor discovered for this enzyme to date. Docking of these compounds into the known structures of human HGPRT in complex with ANP-based inhibitors suggests reasons for the variations in affinity, providing insights for the design of antimalarial drug candidates.