(2'Z-3'E)-6-bromoindirubin-3'-[O-(2-piperazin-1-ylethyl)oxime] | 1067884-45-0

• 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: (2'Z-3'E)-6-bromoindirubin-3'-[O-(2-piperazin-1-ylethyl)oxime]
• 英文别名: (2'Z,3'E)-6-bromoindirubin-3'-[O-(2-piperazine-1-ylethyl)oxime]
• CAS: 1067884-45-0
• 化学式: C₂₂H₂₂BrN₅O₂
• 分子量: 468.353
• InChiKey: HJVDQPRJANOXIX-IVGNLCKYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.86
• 重原子数：
  30.0
• 可旋转键数：
  4.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  77.99
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  (2'Z,3'E)-6-溴靛玉红-3'-肟 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.67h， 生成 (2'Z-3'E)-6-bromoindirubin-3'-[O-(2-piperazin-1-ylethyl)oxime]
  参考文献：
  名称：

  Indirubin Core Structure of Glycogen Synthase Kinase-3 Inhibitors as Novel Chemotype for Intervention with 5-Lipoxygenase

  摘要：

  The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 mu M), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.

  DOI：

  10.1021/jm401740w

文献信息

• 6-Bromoindirubin-3′-oxime derivatives are highly active colistin adjuvants against <i>Klebsiella pneumoniae</i>
  作者：Haoting Li、Anne E. Mattingly、Richard D. Smith、Roberta J. Melander、Robert K. Ernst、Christian Melander

  DOI：10.1039/d2md00370h

  日期：——

  Multidrug resistant (MDR) bacterial infections have become increasingly common, leading clinicians to rely on last-resort antibiotics such as colistin.

  多重耐药（MDR）细菌感染越来越普遍，导致临床医生不得不依赖最后的抗生素，如科利斯汀。
• Soluble 3′,6-Substituted Indirubins with Enhanced Selectivity toward Glycogen Synthase Kinase -3 Alter Circadian Period
  作者：Konstantina Vougogiannopoulou、Yoan Ferandin、Karima Bettayeb、Vassilios Myrianthopoulos、Olivier Lozach、Yunzhen Fan、Carl Hirschie Johnson、Prokopios Magiatis、Alexios-Leandros Skaltsounis、Emmanuel Mikros、Laurent Meijer

  DOI：10.1021/jm800648y

  日期：2008.10.23

  Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective as GSK-3 inhibitors, most indirubins exhibit low water solubility. To address the issue of solubility, we have designed novel analogues of 6-bromo-indirubin-3'-oxime with increased hydrophilicity based on the GSK-3/indirubins cocrystal structures. The new derivatives with an extended amino side chain attached at position 3' showed potent GSK-3 inhibitory activity, enhanced selectivity, and dramatically increased water solubility. Furthermore, some of them displayed little or no cytotoxicity. The new indirubins inhibit GSK-3 in a cellular reporter model. They alter the circadian period measured in rhythmically expressing cell cultures, suggesting that they might constitute tools to investigate circadian rhythm regulation.
• Indirubin Core Structure of Glycogen Synthase Kinase-3 Inhibitors as Novel Chemotype for Intervention with 5-Lipoxygenase
  作者：Carlo Pergola、Nicolas Gaboriaud-Kolar、Nadine Jestädt、Stefanie König、Marina Kritsanida、Anja M. Schaible、Haokun Li、Ulrike Garscha、Christina Weinigel、Dagmar Barz、Kai F. Albring、Otmar Huber、Alexios L. Skaltsounis、Oliver Werz

  DOI：10.1021/jm401740w

  日期：2014.5.8

  The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 mu M), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.