(4-硝基苯基)喹啉-3-基甲基碳酸酯 | 918440-74-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: (4-硝基苯基)喹啉-3-基甲基碳酸酯
• 英文名称: 4-nitrophenyl (quinolin-3-ylmethyl) carbonate
• 英文别名: 4-Nitrophenyl (quinolin-3-yl)methyl carbonate；(4-nitrophenyl) quinolin-3-ylmethyl carbonate
• CAS: 918440-74-1
• 化学式: C₁₇H₁₂N₂O₅
• 分子量: 324.293
• InChiKey: UOYGLFZFSAPYEB-UHFFFAOYSA-N

物化性质

• 沸点：
  533.0±50.0 °C(Predicted)
• 密度：
  1.389±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  94.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (4-硝基苯基)喹啉-3-基甲基碳酸酯 在 lithium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 quinolin-3-ylmethyl (S)-1-(((R)-3-bromo-4,5-dihydroisoxazol-5-yl)methylamino)-3-(5-fluoro-1H-indol-3-yl)-1-oxopropan-2-ylcarbamate
  参考文献：
  名称：

  Structure−Activity Relationship Analysis of the Selective Inhibition of Transglutaminase 2 by Dihydroisoxazoles

  摘要：

  Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, and some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here, we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity and have led to the discovery of an inhibitor with about 50-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S)-dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R) stereoisomer.

  DOI：

  10.1021/jm060839a
• 作为产物：
  描述：

  3-喹啉甲醛 在 N-甲基吗啉 、 锂硼氢 、 乙醇 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 (4-硝基苯基)喹啉-3-基甲基碳酸酯
  参考文献：
  名称：

  Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2

  摘要：

  Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that catalyzes the posttranslational modification of glutamine residues on protein or peptide substrates. A growing body of literature has implicated aberrantly regulated activity of TG2 in the pathogenesis of various human inflammatory, fibrotic, and other diseases. Taken together with the fact that TG2 knockout mice are developmentally and reproductively normal, there is growing interest in the potential use of TG2 inhibitors in the treatment of these conditions. Targeted-covalent inhibitors based on the weakly electrophilic 3-bromo-4,5-dihydroisoxazole (DHI) scaffold have been widely used to study TG2 biology and are well tolerated in vivo, but these compounds have only modest potency, and their selectivity toward other transglutaminase homologues is largely unknown. In the present work, we first profiled the selectivity of existing inhibitors against the most pertinent TG isoforms (TG1, TG3, and FXIIIa). Significant cross-reactivity of these small molecules with TG1 was observed. Structure-activity and -selectivity analyses led to the identification of modifications that improved potency and isoform selectivity. Preliminary pharmacokinetic analysis of the most promising analogues was also undertaken. Our new data provides a clear basis for the rational selection of dihydroisoxazole inhibitors as tools for in vivo biological investigation.

  DOI：

  10.1021/jm501145a

文献信息

• Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2
  作者：Cornelius Klöck、Zachary Herrera、Megan Albertelli、Chaitan Khosla

  DOI：10.1021/jm501145a

  日期：2014.11.13

  Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that catalyzes the posttranslational modification of glutamine residues on protein or peptide substrates. A growing body of literature has implicated aberrantly regulated activity of TG2 in the pathogenesis of various human inflammatory, fibrotic, and other diseases. Taken together with the fact that TG2 knockout mice are developmentally and reproductively normal, there is growing interest in the potential use of TG2 inhibitors in the treatment of these conditions. Targeted-covalent inhibitors based on the weakly electrophilic 3-bromo-4,5-dihydroisoxazole (DHI) scaffold have been widely used to study TG2 biology and are well tolerated in vivo, but these compounds have only modest potency, and their selectivity toward other transglutaminase homologues is largely unknown. In the present work, we first profiled the selectivity of existing inhibitors against the most pertinent TG isoforms (TG1, TG3, and FXIIIa). Significant cross-reactivity of these small molecules with TG1 was observed. Structure-activity and -selectivity analyses led to the identification of modifications that improved potency and isoform selectivity. Preliminary pharmacokinetic analysis of the most promising analogues was also undertaken. Our new data provides a clear basis for the rational selection of dihydroisoxazole inhibitors as tools for in vivo biological investigation.
• Structure−Activity Relationship Analysis of the Selective Inhibition of Transglutaminase 2 by Dihydroisoxazoles
  作者：R. Edward Watts、Mathew Siegel、Chaitan Khosla

  DOI：10.1021/jm060839a

  日期：2006.12.1

  Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, and some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here, we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity and have led to the discovery of an inhibitor with about 50-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S)-dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R) stereoisomer.