(R)-6-ethyl-6-(p-tolyl)benzo[b]pyrrolo[1,2-d][1,4]oxazepin-7(6H)-one | 1452815-87-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: (R)-6-ethyl-6-(p-tolyl)benzo[b]pyrrolo[1,2-d][1,4]oxazepin-7(6H)-one
• 英文别名: (6R)-6-ethyl-6-(4-methylphenyl)pyrrolo[2,1-d][1,5]benzoxazepin-7-one
• CAS: 1452815-87-0
• 化学式: C₂₁H₁₉NO₂
• 分子量: 317.387
• InChiKey: LRKSZHPGBHPTGM-OAQYLSRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  31.2
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (R)-6-ethyl-6-(p-tolyl)benzo[b]pyrrolo[1,2-d][1,4]oxazepin-7(6H)-one 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 作用下， 以 四氯化碳 为溶剂， 反应 7.0h， 生成
  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 、 sodium hydrogen sulfate 、 15-冠醚-5 、 tin(II) chloride dihdyrate 、 乙醇 、 五氯化磷 、 水 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 、 potassium hydroxide 、 sodium hydroxide 、 zinc(II) chloride 、 sodium nitrite 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 61.0h， 生成 (R)-6-ethyl-6-(p-tolyl)benzo[b]pyrrolo[1,2-d][1,4]oxazepin-7(6H)-one
  参考文献：
  名称：

  立体选择性合成6-取代的吡咯并-1,5-苯并恶嗪酮及其类似物的途径

  摘要：

  我们开发了一种新颖且方便的立体选择路径，用于制备吡咯并-1,5-苯并恶嗪酮（PBO）。这一创新途径设想了使用（-）-薄荷醇作为方便的手性助剂和关键的S N Ar，用于立体选择性地制备叔芳基-烷基醚。作为进一步的进步，我们利用这种新构想的合成路线来制备2取代的PBO类似物，以对其自身进行生物学评估或获得各种其他功能化选择。

  DOI：

  10.1016/j.tetlet.2013.07.115

文献信息

• A stereoselective route to 6-substituted pyrrolo-1,5-benzoxazepinones and their analogues
  作者：Margherita Brindisi、Sandra Gemma、Gloria Alfano、Giridhar Kshirsagar、Ettore Novellino、Giuseppe Campiani、Stefania Butini

  DOI：10.1016/j.tetlet.2013.07.115

  日期：2013.9

  developed a novel and convenient stereoselective path for the preparation of pyrrolo-1,5-benzoxazepinones (PBOs). This innovative route envisaged the employment of (−)-menthol as convenient chiral auxiliary and a key SNAr for the stereoselective preparation of a tertiary aryl–alkyl ether. As a further advancement, we exploited this newly conceived synthetic route for the preparation of 2-substituted PBO analogues

  我们开发了一种新颖且方便的立体选择路径，用于制备吡咯并-1,5-苯并恶嗪酮（PBO）。这一创新途径设想了使用（-）-薄荷醇作为方便的手性助剂和关键的S N Ar，用于立体选择性地制备叔芳基-烷基醚。作为进一步的进步，我们利用这种新构想的合成路线来制备2取代的PBO类似物，以对其自身进行生物学评估或获得各种其他功能化选择。
• 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.