6-溴靛玉红 | 667463-60-7

• 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
• 中文名称: 6-溴靛玉红
• 英文名称: 6-Bromoindirubin
• 英文别名: (3Z)-6-bromo-3-(3-oxo-1H-indol-2-ylidene)-1H-indol-2-one
• CAS: 667463-60-7
• 化学式: C₁₆H₉BrN₂O₂
• 分子量: 341.164
• InChiKey: BUPAMFGRFQGRCA-YPKPFQOOSA-N

物化性质

• 熔点：
  >300 °C(Solv: ethyl acetate (141-78-6))
• 沸点：
  520.2±50.0 °C(Predicted)
• 密度：
  1.695±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.42
• 重原子数：
  21.0
• 可旋转键数：
  0.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  58.2
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  6-溴靛玉红 在 吡啶 、 四(三苯基膦)钯 、 盐酸羟胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.5h， 生成 6-Vinylindirubin-3'-oxime
  参考文献：
  名称：

  Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases

  摘要：

  Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources, are potent inhibitors of several kinases, including GSK-3. Using the cocrystal structures of various indirubins with GSK-3beta, CDK2 and CDK5/p25, we have modeled the binding of indirubins within the ATP-binding pocket of these kinases. This modeling approach provided some insight into the molecular basis of indirubins' action and selectivity and allowed us to forecast some improvements of this family of bis-indoles as kinase inhibitors. Predicted molecules, including 6-substituted and 5,6-disubstituted indirubins, were synthesized and evaluated as CDK and GSK-3 inhibitors. Control, kinase-inactive indirubins were obtained by introduction of a methyl substitution on N1.

  DOI：

  10.1021/jm031016d
• 作为产物：
  描述：

  N-(3-bromophenyl)-2-hydroxyiminacetamide 在 硫酸 、 sodium carbonate 作用下， 以 甲醇 为溶剂， 反应 3.25h， 生成 6-溴靛玉红
  参考文献：
  名称：

  Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases

  摘要：

  Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources, are potent inhibitors of several kinases, including GSK-3. Using the cocrystal structures of various indirubins with GSK-3beta, CDK2 and CDK5/p25, we have modeled the binding of indirubins within the ATP-binding pocket of these kinases. This modeling approach provided some insight into the molecular basis of indirubins' action and selectivity and allowed us to forecast some improvements of this family of bis-indoles as kinase inhibitors. Predicted molecules, including 6-substituted and 5,6-disubstituted indirubins, were synthesized and evaluated as CDK and GSK-3 inhibitors. Control, kinase-inactive indirubins were obtained by introduction of a methyl substitution on N1.

  DOI：

  10.1021/jm031016d

文献信息

• [EN] INDIRUBIN-TYPE COMPOUNDS, COMPOSITIONS, AND METHODS FOR THEIR USE<br/>[FR] COMPOSES DE TYPE INDIRUBINE, COMPOSITIONS ET LEURS PROCEDES D'UTILISATION
  申请人：UNIV ROCKEFELLER

  公开号：WO2005041954A1

  公开（公告）日：2005-05-12

  Compounds and compositions including 6-bromo-indirubin, 5-amino-indirubin and N-methyl-indirubins and related indirubin derivatives are provided that are useful as selective modulators of glycogen synthase kinase-3, cyclin-dependent protein kinases or aryl hydrocarbon receptors. Methods of inhibiting or modulating cell growth or cell cycling are provided using the compounds of the invention. In other aspects, compounds and methods for the treatment of protozoan-mediated diseases, Alzheimer's disease and diabetes are provided.

  提供了包括6-溴吲哚红、5-氨基吲哚红和N-甲基吲哚红以及相关吲哚红衍生物的化合物和组合物，这些化合物对于选择性调节糖原合酶激酶-3、细胞周期蛋白激酶或芳香烃受体非常有用。利用本发明的化合物提供了抑制或调节细胞生长或细胞周期的方法。在其他方面，提供了用于治疗原虫介导疾病、阿尔茨海默病和糖尿病的化合物和方法。
• Novel Synthesis of 4- or 6-Substituted Indirubin Derivatives
  作者：Aiying Zhang、Mingfeng Yu、Tian Lan、Zenglu Liu、Zhenmin Mao

  DOI：10.1080/00397910903318591

  日期：2010.9.30

  A simple and convenient route for synthesis of a series of 4- or 6-substituted indirubin derivatives by oxidation and subsequent condensation of indoxyl and isatin is described. Acidic reaction conditions are crucial to the condensation of 4-substituted derivatives, whereas for the condensation of 6-substituted derivatives, both acidic and basic conditions work well.

  描述了通过氧化和随后缩合吲哚酚和靛红来合成一系列 4-或 6-取代的靛玉红衍生物的简单方便的途径。酸性反应条件对 4-取代衍生物的缩合至关重要，而对于 6-取代衍生物的缩合，酸性和碱性条件都适用。
• Biodistribution of Fracture-Targeted GSK3β Inhibitor-Loaded Micelles for Improved Fracture Healing
  作者：Stewart A. Low、Chris V. Galliford、Jiyuan Yang、Philip S. Low、Jindřich Kopeček

  DOI：10.1021/acs.biomac.5b00777

  日期：2015.10.12

  Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone.

  骨折是导致主要疾病和死亡的原因，尤其是在老年人中。与骨质疏松药物相关的并发症以及患者的年龄减缓了骨代谢，使得这些骨折的愈合变得困难。通过使用针对骨折的骨生长促进剂来提高骨折愈合的速度可能具有相当大的应用潜力。天冬氨酸寡肽在生理pH下是带负电荷的分子，能够吸附到羟基磷灰石上，羟基磷灰石是骨的矿物成分。这种一般性吸附在骨代谢最高或者羟基磷灰石新鲜暴露的地方最强。重要的是，这两种情况在骨折部位都非常突出。GSK3β抑制剂是一种强效的合成药物，能够在损伤组织中促进组织修复。不幸的是，它们在系统性给药时可能会引起显著的毒性，并且由于其强烈的疏水性，给药也相当困难。在本文中，我们通过将疏水性的GSK3β抑制剂与亲水性的天冬氨酸八肽通过可水解的键结合，从而解决了这两个问题，生成了一种针对骨折的水溶性药物形式。所产生的两性分子显示出能够聚集成微胶束，延长其循环时间，同时保持其针对骨折的靶向能力。为了测量药代动力学，我们在GSK3β抑制剂的溴位置引入了125I，以最小化任何结构差异。生物分布研究表明，骨折部位的积累相较于健康骨骼增加了超过4倍。
• Syntheses of Indirubins by Aldol Condensation of Isatins with Indoxyl Anion Generated in situ by Lipase-Catalyzed Deacetylation of Indoxyl Acetate
  作者：Takeshi Sugai、Kengo Hanaya、Shuhei Higashibayashi

  DOI：10.3987/com-19-14118

  日期：——

  suppression of the oxidative byproduct formation from indoxyl acetate. Historically, interest in and studies on naturally occurring dyes have been underlying origins of the chemistry of heterocyclic organic compounds. The development of indigo is unambiguously one of the most famous examples. Natural indigo is manufactured from indican (1a), which originates from plants, through a fermentation process via

  靛玉红（产率 76%）、6-溴靛玉红（产率 82%）和 6-溴靛玉红（两步产率 78%）的合成是通过靛红和吲哚酚之间的脂肪酶引发的醛醇缩合实现的以无水厌氧条件下四氢呋喃中阴离子为关键步骤。在三乙胺和 2-丙醇作为酯交换试剂的情况下，通过洋葱伯克霍尔德氏菌脂肪酶 (Amano PS-IM) 催化市售稳定的醋酸吲哚酚脱乙酰化原位产生羟醛供体。目前开发的反应的放大比以前报道的化学羟醛缩合反应更容易，因为分离过程简单并且抑制了乙酸吲哚酚的氧化副产物形成。从历史上看，对天然染料的兴趣和研究一直是杂环有机化合物化学的潜在起源。靛蓝的发展无疑是最著名的例子之一。天然靛蓝是由源自植物的靛蓝 (1a) 通过吲哚酚 (1b) 氧化二聚的发酵过程制成的，如方案 1 所示。该过程伴随着深紫色染料靛玉红的形成（2a），通过另一种氧化中间体，靛红（3a），也如方案1所示。靛玉红本身已从植物中分离出来，已知是中药“当归
• Indirubin-Type Compounds, Compositions, and Methods for Their Use
  申请人：Meijer Laurent

  公开号：US20070276025A1

  公开（公告）日：2007-11-29

  Compounds and compositions including 6-bromo-indirubin, 5-amino-indirubin and N-methyl-indirubins and related indirubin derivatives are provided that are useful as selective modulators of glycogen synthase kinase-3, cyclin-dependent protein kinases or aryl hydrocarbon receptors. Methods of inhibiting or modulating cell growth or cell cycling are provided using the compounds of the invention. In other aspects, compounds and methods for the treatment of protozoan-mediated diseases, Alzheimer's disease and diabetes are provided.

  提供了包括6-溴吲哚红、5-氨基吲哚红和N-甲基吲哚红及相关吲哚红衍生物的化合物和组合物，它们可用作选择性调节糖原合酶激酶-3、周期蛋白依赖性蛋白激酶或芳香族羟基化酶的调节剂。使用本发明的化合物提供了抑制或调节细胞生长或细胞周期的方法。在其他方面，提供了治疗原虫介导疾病、阿尔茨海默病和糖尿病的化合物和方法。