9-[(N-(2-cyanoethyl)-N-(2-phosphonoethyl))-2-aminoethyl]-hypoxanthine | 1383381-54-1

• 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-(2-cyanoethyl)-N-(2-phosphonoethyl))-2-aminoethyl]-hypoxanthine
• 英文别名: 2-[2-cyanoethyl-[2-(6-oxo-1H-purin-9-yl)ethyl]amino]ethylphosphonic acid
• CAS: 1383381-54-1
• 化学式: C₁₂H₁₇N₆O₄P
• 分子量: 340.279
• InChiKey: MXUMOEQVYHYPGP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  144
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  9-[(N-(2-cyanoethyl)-N-(2-phosphonoethyl))-2-aminoethyl]-hypoxanthine 、 L-苯丙氨酸乙酯盐酸盐 在 吡啶 、 三乙胺 、 三苯基膦 作用下， 反应 48.0h， 以37%的产率得到(2S,2'S)-isopropyl-2,2'-{[2-((2-cyanoethyl)(2-(hypoxanthin-9-yl)ethyl)amino)ethyl]phosphoryl}bis(azanediyl)bis(3-phenylpropanoate)
  参考文献：
  名称：

  Aza-acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group As Inhibitors of the Human, Plasmodium falciparum and vivax 6-Oxopurine Phosphoribosyltransferases and Their Prodrugs As Antimalarial Agents

  摘要：

  Hypoxanthineguanine[xanthine] phosphoribosyltransferase (HG[X]PRT) is considered an important target for antimalarial chemotherapy as it is the only pathway for the synthesis of the purine nucleoside monophosphates required for DNA/RNA production. Thus, inhibition of this enzyme should result in cessation of replication. The aza-acyclic nucleoside phosphonates (aza-ANPs) are good inhibitors of Plasmodium falciparum HGXPRT (PfHGXPRT), with K-i values as low as 0.08 and 0.01 mu M for Plasmodium vivax HGPRT (PvHGPRT). Prodrugs of these aza-ANPs exhibit antimalarial activity against Pf lines with IC50 values (0.8-6.0 mu M) and have low cytotoxicity against human cells. Crystal structures of six of these compounds in complex with human HGPRT have been determined. These suggest that the different affinities of these aza-ANPs could be due to the flexibility of the loops surrounding the active site as well as the flexibility of the inhibitors, allowing them to adapt to fit into three binding pockets of the enzyme(s).

  DOI：

  10.1021/jm501416t
• 作为产物：
  描述：

  diethyl 2-((2-cyanoethyl)(2-hydroxyethyl)amino)ethylphosphonate 在 2,6-二甲基吡啶 、 三甲基溴硅烷 、 偶氮二甲酸二异丙酯 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 96.0h， 生成 9-[(N-(2-cyanoethyl)-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

• 6-OXOPURINE PHOSPHORIBOSYLTRANSFERASE INHIBITORS
  申请人：THE UNIVERSITY OF QUEENSLAND

  公开号：US20150099722A1

  公开（公告）日：2015-04-09

  The invention relates to compounds which are useful as inhibitors of 6-oxopurine phosphoribosyltransferases such as hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT).

  本发明涉及一种化合物，该化合物可用作6-氧嘌呤磷酸核糖转移酶的抑制剂，例如次黄嘌呤鸟嘌呤-(黄嘌呤)磷酸核糖转移酶（HG（X）PRT）。
• [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
• US9200020B2
  申请人：——

  公开号：US9200020B2

  公开（公告）日：2015-12-01
• 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.