2-(Diethoxyphosphinyl)-2-methylpropionic Acid | 77124-19-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: 2-(Diethoxyphosphinyl)-2-methylpropionic Acid
• 英文别名: 2-Diethoxyphosphoryl-2-methylpropanoic acid
• CAS: 77124-19-7
• 化学式: C₈H₁₇O₅P
• 分子量: 224.194
• InChiKey: UHTVJYQJYKCAIY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  14
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(Diethoxyphosphinyl)-2-methylpropionic Acid 在 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 苯 为溶剂， 反应 1.0h， 以100%的产率得到C₈H₁₆ClO₄P
  参考文献：
  名称：

  Inhibition of Staphyloxanthin Virulence Factor Biosynthesis in Staphylococcus aureus: In Vitro, in Vivo, and Crystallographic Results

  摘要：

  The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar K-i values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC50 = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections.

  DOI：

  10.1021/jm9001764
• 作为产物：
  描述：

  Triethyl-2-methyl-2-phosphonpropionat 在 乙醇 、 potassium hydroxide 、 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 24.0h， 生成 2-(Diethoxyphosphinyl)-2-methylpropionic Acid
  参考文献：
  名称：

  Inhibition of Staphyloxanthin Virulence Factor Biosynthesis in Staphylococcus aureus: In Vitro, in Vivo, and Crystallographic Results

  摘要：

  The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar K-i values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC50 = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections.

  DOI：

  10.1021/jm9001764

文献信息

• Phosphite-mediated in situ carboxyvinylation: a new general acrylic acid synthesis
  作者：David R. Brittelli

  DOI：10.1021/jo00325a016

  日期：1981.6
• An Efficient Preparation of β-Aryl-β-ketophosphonates by the TFAA/H₃PO₄-Mediated Acylation of Arenes with Phosphonoacetic Acids
  作者：George P. Luke、Christopher K. Seekamp、Zhe-Qing Wang、Bertrand L. Chenard

  DOI：10.1021/jo800973e

  日期：2008.8.1

  [GRAPHICS]beta-Aryl-beta-ketophosphonates can be efficiently prepared in good yield by using a TFAA/85% H(3)PO(4)-mediated acylation of electron-rich arenes with phosphonoacetic acids. The conditions offer advantages over existing methods of preparing these useful compounds by not requiring the use of strong base, cryogenics, or an anhydrous and inert atmosphere. Furthermore, some functional groups not tolerated with the reaction conditions used in existing methods are compatible with the herein described conditions.
• BRITTELLI D. R., J. ORG. CHEM., 1981, 46, NO 12, 2514-2520
  作者：BRITTELLI D. R.

  DOI：——

  日期：——
• [EN] METHODS FOR PREPARING ARYL-SUBSTITUTED KETOPHOSPHONATES<br/>[FR] PROCÉDÉS DE PRÉPARATION DE CÉTOPHOSPHONATES SUBSTITUÉS PAR DES GROUPES ARYLE
  申请人：NEUROGEN CORP

  公开号：WO2008097483A2

  公开（公告）日：2008-08-14

  [EN] Methods are provided for the synthesis of aryl-substituted ketophosphonates of the Formula (I): wherein variables are as described herein. Such compounds are useful as reagents for olefination reactions, and as intermediates in the synthesis of certain biologically active agents.
  [FR] La présente invention a trait à des procédés de synthèse de cétophosphonates substitués par des groupes aryle de formule (I), dans laquelle les variables sont telles que décrites dans les présentes. Lesdits composés se révèlent utiles en tant que réactifs pour les réactions d'oléfination et en tant qu'intermédiaires dans la synthèse de certains agents biologiquement actifs.
• Inhibition of Staphyloxanthin Virulence Factor Biosynthesis in <i>Staphylococcus aureus</i>: In Vitro, in Vivo, and Crystallographic Results
  作者：Yongcheng Song、Chia-I Liu、Fu-Yang Lin、Joo Hwan No、Mary Hensler、Yi-Liang Liu、Wen-Yih Jeng、Jennifer Low、George Y. Liu、Victor Nizet、Andrew H.-J. Wang、Eric Oldfield

  DOI：10.1021/jm9001764

  日期：2009.7.9

  The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar K-i values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC50 = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections.