(2S,5'R)-2-(N-(benzyloxycarbonyl)amino)-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid | 156426-53-8

• 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: (2S,5'R)-2-(N-(benzyloxycarbonyl)amino)-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid
• 英文别名: (5R)-5-[(2S)-2-carboxy-2-(phenylmethoxycarbonylamino)ethyl]-4,5-dihydro-1,2-oxazole-3-carboxylic acid
• CAS: 156426-53-8
• 化学式: C₁₅H₁₆N₂O₇
• 分子量: 336.301
• InChiKey: RFBKJFXJHPJBPZ-MNOVXSKESA-N

物化性质

• 密度：
  1.48±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  135
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S,5'R)-2-(N-(benzyloxycarbonyl)amino)-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid 150.0 ℃ 、133.32 Pa 条件下， 反应 0.08h， 以46%的产率得到(2S,4R)-2-(N-(benzyloxycarbonyl)amino)-5-cyano-4-hydroxypentanoic acid γ-lactone
  参考文献：
  名称：

  Synthesis and Testing of Heterocyclic Analogs of Diaminopimelic Acid (DAP) as Inhibitors of DAP Dehydrogenase and DAP Epimerase

  摘要：

  Substrate analogues were synthesized and examined as inhibitors of diaminopimelic acid (DAP) dehydrogenase from Bacillus sphaericus and of DAP epimerase from Escherichia coli. These enzymes produce meso-DAP (3) (a precursor for L-lysine and for peptidoglycan) from L-tetrahydrodipicolinic acid (1) and LL-DAP (2), respectively. The epimerase was purified by an improved procedure and confirmed to require both carboxyl and both amino groups for substrate recognition using deuterium-exchange experiments with DAP isomers, L-lysine, D-lysine, L-alpha-aminopimelate, and racemic alpha-aminopimelate. An imidazole analogue of DAP, (2S)-2-amino-3-(4-carboxyimidazol-1-yl)propanoic acid (4), was synthesized by condensation of benzyl imidazole-4-carboxylate (8) with N-benzyloxycarbonyl(Cbz)-L-serine beta-lactone (9) (product structure confirmed by X-ray analysis) followed by hydrogenolytic deprotection. Two other analogues, (2S,5'R)-2-amino-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid (5) and its 5'S diastereomer 6, were prepared by condensation of methyl N-Cbz-L-allylglycinate (13) with methyl chlorooximidoacetate (14) followed by separation of isomers and deprotection with NaOH and Me(3)SiCl/NaI. Similar condensation of ethyl chlorooximidoacetate with ethylene and of 14 with ethyl acrylate generated isoxazolines, which were saponified to 2-isoxazoline-3-carboxylic acid (25) and 2-isoxazoline-3,5-dicarboxylic acid (26), respectively. None of the compounds show significant inhibition of DAP epimerase or DAP dehydrogenase with the exception of 6, which is a potent and specific inhibitor of DAP dehydrogenase. At pH 7.5 or 7.8, compound 6 shows competitive inhibition (K-i = 4.2 mu M) with tetrahydrodipicolinic acid (1) for the forward reaction and noncompetitive inhibition (K-i = 23 mu M) with meso-DAP (3) for the reverse process. Preliminary tests for antimicrobial activity demonstrate that 6 inhibits the growth of B. sphaericus, which relies exclusively on DAP dehydrogenase to produce 3.

  DOI：

  10.1021/ja00094a004
• 作为产物：
  描述：

  (S)-(-)-2-氨基-4-戊烯酸 在 4-二甲氨基吡啶 、 三甲基氯硅烷 、 水 、 碳酸氢钠 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 生成 (2S,5'R)-2-(N-(benzyloxycarbonyl)amino)-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid
  参考文献：
  名称：

  Diaminopimelic acid (DAP) analogs bearing isoxazoline moiety as selective inhibitors against meso-diaminopimelate dehydrogenase (m-Ddh) from Porphyromonas gingivalis

  摘要：

  Two diastereomeric analogs (1 and 2) of diaminopimelic acid (DAP) bearing an isoxazoline moiety were synthesized and evaluated for their inhibitory activities against meso-diaminopimelate dehydrogenase (m-Ddh) from the periodontal pathogen, Porphyromonas gingivalis. Compound 2 showed promising inhibitory activity against m-Ddh with an IC50 value of 14.9 mu M at pH 7.8. The two compounds were further tested for their antibacterial activities against a panel of periodontal pathogens, and compound 2 was shown to be selectively potent to P. gingivalis strains W83 and ATCC 33277 with minimum inhibitory concentration (MIC) values of 773 mu M and 1.875 mM, respectively. Molecular modeling studies revealed that the inversion of chirality at the C-5 position of these compounds was the primary reason for their different biological profiles. Based on these preliminary results, we believe that compound 2 has properties consistent with it being a lead compound for developing novel pathogen selective antibiotics to treat periodontal diseases. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2017.06.056

文献信息

• Synthesis and Testing of Heterocyclic Analogs of Diaminopimelic Acid (DAP) as Inhibitors of DAP Dehydrogenase and DAP Epimerase
  作者：Shaun D. Abbott、Patricia Lane-Bell、Kanwar P. S. Sidhu、John C. Vederas

  DOI：10.1021/ja00094a004

  日期：1994.7

  Substrate analogues were synthesized and examined as inhibitors of diaminopimelic acid (DAP) dehydrogenase from Bacillus sphaericus and of DAP epimerase from Escherichia coli. These enzymes produce meso-DAP (3) (a precursor for L-lysine and for peptidoglycan) from L-tetrahydrodipicolinic acid (1) and LL-DAP (2), respectively. The epimerase was purified by an improved procedure and confirmed to require both carboxyl and both amino groups for substrate recognition using deuterium-exchange experiments with DAP isomers, L-lysine, D-lysine, L-alpha-aminopimelate, and racemic alpha-aminopimelate. An imidazole analogue of DAP, (2S)-2-amino-3-(4-carboxyimidazol-1-yl)propanoic acid (4), was synthesized by condensation of benzyl imidazole-4-carboxylate (8) with N-benzyloxycarbonyl(Cbz)-L-serine beta-lactone (9) (product structure confirmed by X-ray analysis) followed by hydrogenolytic deprotection. Two other analogues, (2S,5'R)-2-amino-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid (5) and its 5'S diastereomer 6, were prepared by condensation of methyl N-Cbz-L-allylglycinate (13) with methyl chlorooximidoacetate (14) followed by separation of isomers and deprotection with NaOH and Me(3)SiCl/NaI. Similar condensation of ethyl chlorooximidoacetate with ethylene and of 14 with ethyl acrylate generated isoxazolines, which were saponified to 2-isoxazoline-3-carboxylic acid (25) and 2-isoxazoline-3,5-dicarboxylic acid (26), respectively. None of the compounds show significant inhibition of DAP epimerase or DAP dehydrogenase with the exception of 6, which is a potent and specific inhibitor of DAP dehydrogenase. At pH 7.5 or 7.8, compound 6 shows competitive inhibition (K-i = 4.2 mu M) with tetrahydrodipicolinic acid (1) for the forward reaction and noncompetitive inhibition (K-i = 23 mu M) with meso-DAP (3) for the reverse process. Preliminary tests for antimicrobial activity demonstrate that 6 inhibits the growth of B. sphaericus, which relies exclusively on DAP dehydrogenase to produce 3.
• Diaminopimelic acid (DAP) analogs bearing isoxazoline moiety as selective inhibitors against meso-diaminopimelate dehydrogenase (m-Ddh) from Porphyromonas gingivalis
  作者：Hongguang Ma、Victoria N. Stone、Huiqun Wang、Glen E. Kellogg、Ping Xu、Yan Zhang

  DOI：10.1016/j.bmcl.2017.06.056

  日期：2017.8

  Two diastereomeric analogs (1 and 2) of diaminopimelic acid (DAP) bearing an isoxazoline moiety were synthesized and evaluated for their inhibitory activities against meso-diaminopimelate dehydrogenase (m-Ddh) from the periodontal pathogen, Porphyromonas gingivalis. Compound 2 showed promising inhibitory activity against m-Ddh with an IC50 value of 14.9 mu M at pH 7.8. The two compounds were further tested for their antibacterial activities against a panel of periodontal pathogens, and compound 2 was shown to be selectively potent to P. gingivalis strains W83 and ATCC 33277 with minimum inhibitory concentration (MIC) values of 773 mu M and 1.875 mM, respectively. Molecular modeling studies revealed that the inversion of chirality at the C-5 position of these compounds was the primary reason for their different biological profiles. Based on these preliminary results, we believe that compound 2 has properties consistent with it being a lead compound for developing novel pathogen selective antibiotics to treat periodontal diseases. Published by Elsevier Ltd.