3-(1,1,2-Trimethyl-1,2-dihydro-[1,2]oxazino[5,4-b]indol-5(4H)-yl)propanoic acid | 1420476-13-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 3-(1,1,2-Trimethyl-1,2-dihydro-[1,2]oxazino[5,4-b]indol-5(4H)-yl)propanoic acid
• 英文别名: 3-(1,1,2-trimethyl-4H-oxazino[5,4-b]indol-5-yl)propanoic acid
• CAS: 1420476-13-6
• 化学式: C₁₆H₂₀N₂O₃
• 分子量: 288.346
• InChiKey: LKMAHLIDCLEXAS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  54.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-甲羟基吲哚 在 咪唑 、 三丁基膦 、 四丁基氟化铵 、 水 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 cesium fluoride 、 lithium hydroxide 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 重水 为溶剂， 生成 3-(1,1,2-Trimethyl-1,2-dihydro-[1,2]oxazino[5,4-b]indol-5(4H)-yl)propanoic acid
  参考文献：
  名称：

  用于蛋白质化学修饰的 Pictet-Spengler 连接。

  摘要：

  醛和酮功能化蛋白质是开发化学改性生物治疗剂和蛋白质材料的有吸引力的底物。它们的反应性羰基通常与α效应亲核试剂（例如取代的肼和烷氧基胺）共轭，分别生成腙和肟。然而，由此产生的 C=N 键在生理相关条件下易于水解，这限制了此类缀合物在生物系统中的应用。在这里，我们介绍了基于醛和色胺亲核试剂的经典 Pictet-Spengler 反应的 Pictet-Spengler 连接。连接利用醛和烷氧基胺的生物正交反应形成中间体氧亚胺离子；该中间体与吲哚亲核试剂形成分子内 CC 键，形成水解稳定的奥沙咔啉产物。我们使用该反应对乙醛酰和甲酰甘氨酸功能化蛋白质进行位点特异性化学修饰，包括治疗性单克隆抗体赫赛汀的醛标记变体。结合位点特异性将醛引入蛋白质的技术，Pictet-Spengler 连接提供了一种产生用于医疗和材料应用的稳定生物偶联物的方法。

  DOI：

  10.1073/pnas.1213186110

文献信息

• PICTET-SPENGLER LIGATION FOR PROTEIN CHEMICAL MODIFICATION
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20150291699A1

  公开（公告）日：2015-10-15

  Aldehyde- and ketone-functionalized proteins are promising new substrates for the development of chemically modified biotherapeutics and protein-based materials. Their reactive carbonyl groups are typically conjugated with a-effect nucleophiles, such as substituted hydrazines and alkoxyamines, to generate hydrazones and oximes, respectively. However, the resulting C═N linkages are susceptible to hydrolysis under physiologically relevant conditions, which limits their utility in biological systems. Here we introduce a Pictet-Spengler ligation that is based on the classic Pictet-Spengler reaction of aldehydes and tryptamine nucleophiles. The ligation exploits the bioorthogonal reaction of aldehydes and alkoxyamines to form an intermediate oxyiminium ion; this intermediate undergoes intramolecular C—C bond formation with an indole nucleophile to form an oxacarboline product that is hydrolytically stable. The reaction was utilized for site-specific chemical modification of glyoxal- and formylglycine-functionalized proteins, including an aldehyde-tagged variant of the therapeutic monoclonal antibody Herceptin. In conjunction with techniques for site-specific introduction of aldehydes into proteins, the Pictet-Spengler ligation offers a new means to generate stable bioconjugates for medical and materials applications.

  醛和酮官能团化的蛋白质是开发化学修饰生物治疗药物和基于蛋白质的材料的有前途的新底物。它们的反应性羰基基团通常与a-效应亲核试剂（如取代的肼和烷氧胺）共轭，分别生成肼和肟。然而，所得到的C═N键在生理条件下易于水解，这限制了它们在生物系统中的实用性。在这里，我们介绍了一种基于经典的醛和色胺亲核试剂的Pictet-Spengler连接反应。该连接反应利用了醛和烷氧胺的生物正交反应形成中间体氧肟离子；该中间体通过与吲哚亲核试剂的分子内C—C键形成，形成一个水解稳定的氧杂环丙烷产物。该反应被用于对丙二醛和甲酰甘氨酸官能化的蛋白质进行位点特异性化学修饰，包括治疗性单克隆抗体Herceptin的醛标记变体。结合蛋白质内醛的位点特异性引入技术，Pictet-Spengler连接反应为生成稳定的生物共轭物提供了一种新的手段，用于医学和材料应用。
• US9605078B2
  申请人：——

  公开号：US9605078B2

  公开（公告）日：2017-03-28
• [EN] PICTET-SPENGLER LIGATION FOR PROTEIN CHEMICAL MODIFICATION<br/>[FR] LIGATURE PICTET-SPENGLER POUR LA MODIFICATION CHIMIQUE DE PROTÉINES
  申请人：UNIV CALIFORNIA

  公开号：WO2014078733A1

  公开（公告）日：2014-05-22

  Aldehyde- and ketone-functionalized proteins are promising new substrates for the development of chemically modified biotherapeutics and protein-based materials. Their reactive carbonyl groups are typically conjugated with a-effect nucleophiles, such as substituted hydrazines and alkoxyamines, to generate hydrazones and oximes, respectively. However, the resulting C=N linkages are susceptible to hydrolysis under physiologically relevant conditions, which limits their utility in biological systems. Here we introduce a Pictet-Spengler ligation that is based on the classic Pictet-Spengler reaction of aldehydes and tryptamine nucleophiles. The ligation exploits the bioorthogonal reaction of aldehydes and alkoxyamines to form an intermediate oxyiminium ion; this intermediate undergoes intramolecular C-C bond formation with an indole nucleophile to form an oxacarboline product that is hydrolytically stable. The reaction was utilized for site-specific chemical modification of glyoxal- and formylglycine-functionalized proteins, including an aldehyde-tagged variant of the therapeutic monoclonal antibody Herceptin. In conjunction with techniques for site-specific introduction of aldehydes into proteins, the Pictet-Spengler ligation offers a new means to generate stable bioconjugates for medical and materials applications.
• A Pictet-Spengler ligation for protein chemical modification
  作者：Paresh Agarwal、Joep van der Weijden、Ellen M. Sletten、David Rabuka、Carolyn R. Bertozzi

  DOI：10.1073/pnas.1213186110

  日期：2013.1.2

  Their reactive carbonyl groups are typically conjugated with alpha-effect nucleophiles, such as substituted hydrazines and alkoxyamines, to generate hydrazones and oximes, respectively. However, the resulting C=N linkages are susceptible to hydrolysis under physiologically relevant conditions, which limits the utility of such conjugates in biological systems. Here we introduce a Pictet-Spengler ligation

  醛和酮功能化蛋白质是开发化学改性生物治疗剂和蛋白质材料的有吸引力的底物。它们的反应性羰基通常与α效应亲核试剂（例如取代的肼和烷氧基胺）共轭，分别生成腙和肟。然而，由此产生的 C=N 键在生理相关条件下易于水解，这限制了此类缀合物在生物系统中的应用。在这里，我们介绍了基于醛和色胺亲核试剂的经典 Pictet-Spengler 反应的 Pictet-Spengler 连接。连接利用醛和烷氧基胺的生物正交反应形成中间体氧亚胺离子；该中间体与吲哚亲核试剂形成分子内 CC 键，形成水解稳定的奥沙咔啉产物。我们使用该反应对乙醛酰和甲酰甘氨酸功能化蛋白质进行位点特异性化学修饰，包括治疗性单克隆抗体赫赛汀的醛标记变体。结合位点特异性将醛引入蛋白质的技术，Pictet-Spengler 连接提供了一种产生用于医疗和材料应用的稳定生物偶联物的方法。