(2S,5'S)-2-amino-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,5'S)-2-amino-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid
• 英文别名: (5S)-5-[(2S)-2-amino-2-carboxyethyl]-4,5-dihydro-1,2-oxazole-3-carboxylic acid
• 化学式: C₇H₁₀N₂O₅
• 分子量: 202.167
• InChiKey: AUXNPKGXCSBLJK-IMJSIDKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.4
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  122
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (S)-(-)-2-氨基-4-戊烯酸 在 盐酸 、 4-二甲氨基吡啶 、 sodium hydroxide 、 三甲基氯硅烷 、 sodium carbonate 、 三乙胺 、 sodium iodide 作用下， 以 乙醚 、 氯仿 、 乙腈 为溶剂， 反应 45.5h， 生成 (2S,5'S)-2-amino-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid
  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

文献信息

• Design, Synthesis, and Pharmacological Characterization of Novel, Potent NMDA Receptor Antagonists
  作者：Paola Conti、Marco De Amici、Giovanni Grazioso、Gabriella Roda、Federico F. Barberis Negra、Birgitte Nielsen、Tine B. Stensbøl、Ulf Madsen、Hans Bräuner-Osborne、Karla Frydenvang、Giovambattista De Sarro、Lucio Toma、Carlo De Micheli

  DOI：10.1021/jm049409f

  日期：2004.12.1

  The two diastereomeric pairs of acidic amino acids 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid (8A/8B) and 4-(2-amino-2-carboxyethyl)-5,5-dimethyl-4,5-dihydroisoxazole-3-carboxylic acid (10A/10B) were prepared via a strategy based on a 1,3-dipolar cycloaddition. The four amino acids were tested at ionotropic and metabotropic glutamate receptors. None of the compounds was active

  酸性氨基酸5-（2-氨基-2-羧乙基）-4,5-二氢异恶唑-3-羧酸（8A / 8B）和4-（2-氨基-2-羧乙基）-5的两个非对映异构体对，通过基于1，3-偶极环加成的策略制备5-二甲基-4，5-二氢异恶唑-3-羧酸（10A / 10B）。在离子型和代谢型谷氨酸受体上测试了这四个氨基酸。这些化合物都没有以1 mM的活性对代谢型受体（在CHO细胞系中表达的mGluR1，-2，-4和-5）有活性，既没有激动剂也没有拮抗剂。相反，当在离子型谷氨酸受体上测试时，一对立体异构体8A / 8B对NMDA受体显示出显着的亲和力，拮抗力和选择性。事实证明，8A的亲和力是非对映体8B的亲和力的5倍（K（i）值分别为0.21和0.96 microM）。此外，在DBA / 2小鼠体内试验中，化合物8A和8B表现出值得注意的抗惊厥活性。衍生物10A对所有离子型谷氨酸受体均无活性，而其立体异构体10B则与NMDA和AMPA受体均具有可捕捉的结合。
• Synthesis, Binding Affinity at Glutamic Acid Receptors, Neuroprotective Effects, and Molecular Modeling Investigation of Novel Dihydroisoxazole Amino Acids
  作者：Paola Conti、Marco De Amici、Giovanni Grazioso、Gabriella Roda、Andrea Pinto、Kasper Bø Hansen、Birgitte Nielsen、Ulf Madsen、Hans Bräuner-Osborne、Jan Egebjerg、Valentina Vestri、Domenico E. Pellegrini-Giampietro、Pauline Sibille、Francine C. Acher、Carlo De Micheli

  DOI：10.1021/jm0504499

  日期：2005.10.1

  lic acid(+)-4, (-)-4, (+)-5, and (-)-5 were prepared by stereoselective synthesis of two pairs of enantiomers, which were subsequently resolved by enzymatic procedures. These four stereoisomers and the four stereoisomers of the bicyclic analogue 5-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylic acid (+)-2, (-)-2, (+)-3, and (-)-3 were tested at ionotropic and metabotropic glutamate

  5-（2-氨基-2-羧乙基）-4,5-二氢异恶唑-3-羧酸（+）-4，（-）-4，（+）-5和（-）-5的四种立体异构体通过两对对映异构体的立体选择性合成制备了二甲基对苯二酚，随后通过酶促方法将其拆分。双环类似物5-氨基-4,5,6,6a-四氢-3aH-环戊[d]异恶唑-3,5-二羧酸（+）-2，（-）-2的这四个立体异构体和四个立体异构体，（+）-3和（-）-3在离子型和代谢型谷氨酸受体亚型中进行了测试。当在氧葡萄糖剥夺（OGD）细胞培养测试中进行测试时，最有效的NMDA受体拮抗剂[（+）-2，（-）-4和（+）-5]显示出显着的神经保护作用。使用表达含有NR1亚基和NR2A的克隆的大鼠NMDA受体的非洲爪蟾卵母细胞初步测定了相同的化合物，NR2B，NR2C或NR2D亚基。在该测定中，所有三种衍生物均表现出较高的拮抗剂效价，优先考虑NR2A和NR2B亚型，而衍生物（-）-4表现为最有效的
• 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.