(R,S)-1-hydroxyethylphosphonate cyclohexylamine | 119295-29-3

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (R,S)-1-hydroxyethylphosphonate cyclohexylamine
• 英文别名: cyclohexanamine;1-hydroxyethylphosphonic acid
• CAS: 119295-29-3
• 化学式: C₂H₇O₄P*C₆H₁₃N
• 分子量: 225.225
• InChiKey: SGXMLVGVENDZNV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.78
• 重原子数：
  14.0
• 可旋转键数：
  1.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  103.78
• 氢给体数：
  4.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (R,S)-1-hydroxyethylphosphonate cyclohexylamine 在 AG 50W-X₈ (Na⁺ form) 作用下， 以0.224 g的产率得到disodium (R,S)-1-hydroxyethylphosphonate
  参考文献：
  名称：

  Potent Inhibition of Mandelate Racemase by a Fluorinated Substrate-Product Analogue with a Novel Binding Mode

  摘要：

  Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg2+-dependent 1,1-proton transfer that interconverts the enantiomers of mandelate. Because trifluorolactate is also a substrate of MR, we anticipated that replacing the phenyl rings of the competitive, substrate-product analogue inhibitor benzilate (K-i = 0.7 mM) with trifluoromethyl groups might furnish an inhibitor. Surprisingly, the substrate-product analogue 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoate (TFHTP) was a potent competitive inhibitor [K-i = 27 +/- 4 mu M; cf. K-m = 1.2 mM for both (R)-mandelate and (R)-trifluorolactate]. To understand the origins of this high binding affinity, we determined the X-ray crystal structure of the MR TFHTP complex to 1.68 angstrom resolution. Rather than chelating the active site Mg2+ with its glycolate moiety, like other ground state analogues, TFHTP exhibited a novel binding mode with the two trifluoromethyl groups closely packed against the 20s loop and the carboxylate bridging the two active site Bronsted acid base catalysts Lys 166 and His 297. Recognizing that positioning a carboxylate between the Bronsted acid base catalysts could yield an inhibitor, we showed that tartronate was a competitive inhibitor of MR (K-i = 1.8 +/- 0.1 mM). The X-ray crystal structure of the MR-tartronate complex (1.80 angstrom resolution) revealed that the glycolate moiety of tartronate chelated the Mg2+ and that the carboxylate bridged Lys 166 and His 297. Models of tartronate in monomers A and B of the crystal structure mimicked the binding orientations of (S)-mandelate and that anticipated for (R)-mandelate, respectively. For the latter monomer, the 20s loop appeared to be disordered, as it also did in the X-ray structure of the MR triple mutant (C92S/C264S/K166C) complexed with benzilate, which was determined to 1.89 angstrom resolution. These observations indicate that the 20s loop likely undergoes a significant conformational change upon binding (R)-mandelate. In general, our observations suggest that inhibitors of other enolase superfamily enzymes may be designed to capitalize on the recognition of the active site Bronsted acid base catalysts as binding determinants.

  DOI：

  10.1021/bi401703h
• 作为产物：
  描述：

  (1-羟基乙基)膦酸二甲基酯 、 环己胺 在 三甲基溴硅烷 作用下， 以 乙腈 、 1,4-二氧六环 、 水 为溶剂， 反应 2.0h， 生成 (R,S)-1-hydroxyethylphosphonate cyclohexylamine
  参考文献：
  名称：

  Potent Inhibition of Mandelate Racemase by a Fluorinated Substrate-Product Analogue with a Novel Binding Mode

  摘要：

  Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg2+-dependent 1,1-proton transfer that interconverts the enantiomers of mandelate. Because trifluorolactate is also a substrate of MR, we anticipated that replacing the phenyl rings of the competitive, substrate-product analogue inhibitor benzilate (K-i = 0.7 mM) with trifluoromethyl groups might furnish an inhibitor. Surprisingly, the substrate-product analogue 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoate (TFHTP) was a potent competitive inhibitor [K-i = 27 +/- 4 mu M; cf. K-m = 1.2 mM for both (R)-mandelate and (R)-trifluorolactate]. To understand the origins of this high binding affinity, we determined the X-ray crystal structure of the MR TFHTP complex to 1.68 angstrom resolution. Rather than chelating the active site Mg2+ with its glycolate moiety, like other ground state analogues, TFHTP exhibited a novel binding mode with the two trifluoromethyl groups closely packed against the 20s loop and the carboxylate bridging the two active site Bronsted acid base catalysts Lys 166 and His 297. Recognizing that positioning a carboxylate between the Bronsted acid base catalysts could yield an inhibitor, we showed that tartronate was a competitive inhibitor of MR (K-i = 1.8 +/- 0.1 mM). The X-ray crystal structure of the MR-tartronate complex (1.80 angstrom resolution) revealed that the glycolate moiety of tartronate chelated the Mg2+ and that the carboxylate bridged Lys 166 and His 297. Models of tartronate in monomers A and B of the crystal structure mimicked the binding orientations of (S)-mandelate and that anticipated for (R)-mandelate, respectively. For the latter monomer, the 20s loop appeared to be disordered, as it also did in the X-ray structure of the MR triple mutant (C92S/C264S/K166C) complexed with benzilate, which was determined to 1.89 angstrom resolution. These observations indicate that the 20s loop likely undergoes a significant conformational change upon binding (R)-mandelate. In general, our observations suggest that inhibitors of other enolase superfamily enzymes may be designed to capitalize on the recognition of the active site Bronsted acid base catalysts as binding determinants.

  DOI：

  10.1021/bi401703h