diethyl (difluoro(4'-((aminooxy)methyl)-1,1'-biphenyl-3-yl)methyl)phosphonate | 1290543-14-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: diethyl (difluoro(4'-((aminooxy)methyl)-1,1'-biphenyl-3-yl)methyl)phosphonate
• 英文别名: O-[[4-[3-[diethoxyphosphoryl(difluoro)methyl]phenyl]phenyl]methyl]hydroxylamine
• CAS: 1290543-14-4
• 化学式: C₁₈H₂₂F₂NO₄P
• 分子量: 385.348
• InChiKey: OAZSEZWNGVKPGW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  70.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  diethyl (difluoro(4'-((aminooxy)methyl)-1,1'-biphenyl-3-yl)methyl)phosphonate 在 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以52%的产率得到((4'-((aminooxy)methyl)-[1,1'-biphenyl]-3-yl)difluoromethyl)phosphonic acid
  参考文献：
  名称：

  Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase

  摘要：

  Our current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 mu M) was converted from a subs trate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid, and by attachment of an aminooxy handle for further structural optimization by mime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequenly employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition Of intracellular Y pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.

  DOI：

  10.1021/jm200022g
• 作为产物：
  描述：

  4-羟甲基苯硼酸 在 四(三苯基膦)钯 、 偶氮二甲酸二异丙酯 、 potassium carbonate 、 一水合肼 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 4.0h， 生成 diethyl (difluoro(4'-((aminooxy)methyl)-1,1'-biphenyl-3-yl)methyl)phosphonate
  参考文献：
  名称：

  Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase

  摘要：

  Our current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 mu M) was converted from a subs trate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid, and by attachment of an aminooxy handle for further structural optimization by mime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequenly employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition Of intracellular Y pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.

  DOI：

  10.1021/jm200022g

文献信息

• Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the <i>Yersinia pestis</i> Outer Protein H (YopH) Phosphatase
  作者：Medhanit Bahta、George T. Lountos、Beverly Dyas、Sung-Eun Kim、Robert G. Ulrich、David S. Waugh、Terrence R. Burke

  DOI：10.1021/jm200022g

  日期：2011.4.28

  Our current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 mu M) was converted from a subs trate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid, and by attachment of an aminooxy handle for further structural optimization by mime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequenly employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition Of intracellular Y pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.