(3E)-5-bromo-3-(furan-2-ylmethylidene)-1H-indol-2-one

• 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: (3E)-5-bromo-3-(furan-2-ylmethylidene)-1H-indol-2-one
• 化学式: C₁₃H₈BrNO₂
• 分子量: 290.116
• InChiKey: CBYUHHGMVIHGFQ-YRNVUSSQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  42.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3E)-5-bromo-3-(furan-2-ylmethylidene)-1H-indol-2-one 在 tris(dibenzylideneacetone)dipalladium (0) 、 三(邻甲基苯基)磷 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 (S)-5-(5-(2-amino-3-phenylpropoxy)pyridin-3-yl)-3-(furan-2-ylmethylene)indolin-2-one
  参考文献：
  名称：

  Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

  摘要：

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  DOI：

  10.1021/jm0701019
• 作为产物：
  描述：

  5-溴靛红 在 哌啶 、 一水合肼 作用下， 以 乙醇 为溶剂， 反应 8.5h， 生成 (3E)-5-bromo-3-(furan-2-ylmethylidene)-1H-indol-2-one
  参考文献：
  名称：

  取代吲哚啉-2-酮作为p90核糖体S6蛋白激酶2（RSK2）抑制剂：分子对接模拟和结构-活性关系分析

  摘要：

  设计并合成了一系列新型的针对p90核糖体S6蛋白激酶2（RSK2）的吲哚-2-酮抑制剂，并研究了它们的构效关系（SAR）。最有效的抑制剂化合物3s对RSK2表现出有效的抑制作用，IC 50值为0.5μM，对23种激酶表现出令人满意的选择性。这些抑制剂与RSK2的相互作用是基于拟议的结合姿势和分子对接模拟研究的。四种化合物和六种化合物分别显示出对PC 3细胞和MCF-7细胞适度的抗增殖活性。

  DOI：

  10.1016/j.bmc.2013.01.047

文献信息

• USE OF NOVEL NEUROPROTECTIVE 3-SUBSTITUTED INDOLONE COMPOSITIONS
  申请人：D'Mello Santosh R.

  公开号：US20100298376A1

  公开（公告）日：2010-11-25

  The present invention provides compositions and methods of synthesizing optionally substituted 3-substituted indolin-2-ones and methods to employ the resultant compounds to protect against neurodegeneration including diseases such as Alzheimer's disease, Parkinson's disease, or Huntington's disease, and conditions such as ischemic stroke.
• Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension
  作者：Gui-Dong Zhu、Viraj B. Gandhi、Jianchun Gong、Sheela Thomas、Keith W. Woods、Xiaohong Song、Tongmei Li、R. Bruce Diebold、Yan Luo、Xuesong Liu、Ran Guan、Vered Klinghofer、Eric F. Johnson、Jennifer Bouska、Amanda Olson、Kennan C. Marsh、Vincent S. Stoll、Mulugeta Mamo、James Polakowski、Thomas J. Campbell、Ruth L. Martin、Gary A. Gintant、Thomas D. Penning、Qun Li、Saul H. Rosenberg、Vincent L. Giranda

  DOI：10.1021/jm0701019

  日期：2007.6.1

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.
• Substituted indolin-2-ones as p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors: Molecular docking simulation and structure–activity relationship analysis
  作者：Ye Zhong、Mengzhu Xue、Xue Zhao、Jun Yuan、Xiaofeng Liu、Jin Huang、Zhenjiang Zhao、Honglin Li、Yufang Xu

  DOI：10.1016/j.bmc.2013.01.047

  日期：2013.4

  series of novel indolin-2-ones inhibitors against p90 ribosomal S6 protein kinase 2 (RSK2) were designed and synthesized and their structure–activity relationship (SAR) was studied. The most potent inhibitor, compound 3s, exhibited potent inhibition against RSK2 with an IC50 value of 0.5 μM and presented a satisfactory selectivity against 23 kinases. The interactions of these inhibitors with RSK2 were

  设计并合成了一系列新型的针对p90核糖体S6蛋白激酶2（RSK2）的吲哚-2-酮抑制剂，并研究了它们的构效关系（SAR）。最有效的抑制剂化合物3s对RSK2表现出有效的抑制作用，IC 50值为0.5μM，对23种激酶表现出令人满意的选择性。这些抑制剂与RSK2的相互作用是基于拟议的结合姿势和分子对接模拟研究的。四种化合物和六种化合物分别显示出对PC 3细胞和MCF-7细胞适度的抗增殖活性。