α-ethyl-α-hydroxy-4-methylbenzeneacetic acid | 1309687-06-6

• 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: α-ethyl-α-hydroxy-4-methylbenzeneacetic acid
• 英文别名: (2S)-2-hydroxy-2-(4-methylphenyl)butanoic acid
• CAS: 1309687-06-6
• 化学式: C₁₁H₁₄O₃
• 分子量: 194.23
• InChiKey: XOTXRPRJVXDSMD-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  α-ethyl-α-hydroxy-4-methylbenzeneacetic acid 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 五氯化磷 、 sodium hydride 、 potassium carbonate 、 sodium hydrogensulfite 、 溶剂黄146 、 tin(ll) chloride 、 sodium hydroxide 、 sodium nitrite 作用下， 以 四氢呋喃 、 四氯化碳 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 56.0h， 生成 (S)-NSD438
  参考文献：
  名称：

  Site-directed Mutagenesis of Key Residues Unveiled a Novel Allosteric Site on Human Adenosine Kinase for Pyrrolobenzoxa(thia)zepinone Non-Nucleoside Inhibitors

  摘要：

  Most nucleoside kinases, besides the catalytic domain, feature an allosteric domain which modulates their activity. Generally, non‐substrate analogs, interacting with allosteric sites, represent a major opportunity for developing more selective and safer therapeutics. We recently developed a series of non‐nucleoside non‐competitive inhibitors of human adenosine kinase (hAK), based on a pyrrolobenzoxa(thia)zepinone scaffold. Based on computational analysis, we hypothesized the existence of a novel allosteric site on hAK, topographically distinct from the catalytic site. In this study, we have adopted a multidisciplinary approach including molecular modeling, biochemical studies, and site‐directed mutagenesis to validate our hypothesis. Based on a three‐dimensional model of interaction between hAK and our molecules, we designed, cloned, and expressed specific, single and double point mutants of hAK (Q74A, Q78A, H107A, K341A, F338A, and Q74A‐F338A). Kinetic characterization of recombinant enzymes indicated that these mutations did not affect enzyme functioning; conversely, mutated enzymes are endowed of reduced susceptibility to our non‐nucleoside inhibitors, while maintaining comparable affinity for nucleoside inhibitors to the wild‐type enzyme. This study represents the first characterization and validation of a novel allosteric site in hAK and may pave the way to the development of novel selective and potent non‐nucleoside inhibitors of hAK endowed with therapeutic potential.

  DOI：

  10.1111/cbdd.12630
• 作为产物：
  描述：

  2-(4-甲基苯基)-2-氧代乙酸乙酯 在 titanium(IV) isopropylate 、 水 、 potassium hydroxide 、 zinc(II) chloride 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 36.0h， 生成 α-ethyl-α-hydroxy-4-methylbenzeneacetic acid
  参考文献：
  名称：

  Site-directed Mutagenesis of Key Residues Unveiled a Novel Allosteric Site on Human Adenosine Kinase for Pyrrolobenzoxa(thia)zepinone Non-Nucleoside Inhibitors

  摘要：

  Most nucleoside kinases, besides the catalytic domain, feature an allosteric domain which modulates their activity. Generally, non‐substrate analogs, interacting with allosteric sites, represent a major opportunity for developing more selective and safer therapeutics. We recently developed a series of non‐nucleoside non‐competitive inhibitors of human adenosine kinase (hAK), based on a pyrrolobenzoxa(thia)zepinone scaffold. Based on computational analysis, we hypothesized the existence of a novel allosteric site on hAK, topographically distinct from the catalytic site. In this study, we have adopted a multidisciplinary approach including molecular modeling, biochemical studies, and site‐directed mutagenesis to validate our hypothesis. Based on a three‐dimensional model of interaction between hAK and our molecules, we designed, cloned, and expressed specific, single and double point mutants of hAK (Q74A, Q78A, H107A, K341A, F338A, and Q74A‐F338A). Kinetic characterization of recombinant enzymes indicated that these mutations did not affect enzyme functioning; conversely, mutated enzymes are endowed of reduced susceptibility to our non‐nucleoside inhibitors, while maintaining comparable affinity for nucleoside inhibitors to the wild‐type enzyme. This study represents the first characterization and validation of a novel allosteric site in hAK and may pave the way to the development of novel selective and potent non‐nucleoside inhibitors of hAK endowed with therapeutic potential.

  DOI：

  10.1111/cbdd.12630

文献信息

• Alkaloid induced asymmetric electrocarboxylation of 4-methylpropiophenone
  作者：Shu-Feng Zhao、Mei-Xia Zhu、Kai Zhang、Huan Wang、Jia-Xing Lu

  DOI：10.1016/j.tetlet.2011.03.076

  日期：2011.5

  The alkaloid-induced electrocarboxylation of 4-methylpropiophenone is examined in mild conditions. Comparative studies with several inductors indicate that the efficient enantiodiscrimination of the electrocarboxylation depends on the nucleophilic quinuclidine nitrogen atom and the OH group of the inductors. (C) 2011 Elsevier Ltd. All rights reserved.
• Site-directed Mutagenesis of Key Residues Unveiled a Novel Allosteric Site on Human Adenosine Kinase for Pyrrolobenzoxa(thia)zepinone Non-Nucleoside Inhibitors
  作者：Lida Savi、Margherita Brindisi、Gloria Alfano、Stefania Butini、Valeria La Pietra、Ettore Novellino、Luciana Marinelli、Andrea Lossani、Federico Focher、Caterina Cavella、Giuseppe Campiani、Sandra Gemma

  DOI：10.1111/cbdd.12630

  日期：2016.1

  Most nucleoside kinases, besides the catalytic domain, feature an allosteric domain which modulates their activity. Generally, non‐substrate analogs, interacting with allosteric sites, represent a major opportunity for developing more selective and safer therapeutics. We recently developed a series of non‐nucleoside non‐competitive inhibitors of human adenosine kinase (hAK), based on a pyrrolobenzoxa(thia)zepinone scaffold. Based on computational analysis, we hypothesized the existence of a novel allosteric site on hAK, topographically distinct from the catalytic site. In this study, we have adopted a multidisciplinary approach including molecular modeling, biochemical studies, and site‐directed mutagenesis to validate our hypothesis. Based on a three‐dimensional model of interaction between hAK and our molecules, we designed, cloned, and expressed specific, single and double point mutants of hAK (Q74A, Q78A, H107A, K341A, F338A, and Q74A‐F338A). Kinetic characterization of recombinant enzymes indicated that these mutations did not affect enzyme functioning; conversely, mutated enzymes are endowed of reduced susceptibility to our non‐nucleoside inhibitors, while maintaining comparable affinity for nucleoside inhibitors to the wild‐type enzyme. This study represents the first characterization and validation of a novel allosteric site in hAK and may pave the way to the development of novel selective and potent non‐nucleoside inhibitors of hAK endowed with therapeutic potential.