N,3-bis(3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N,3-bis(3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
• 英文别名: N-(3-hydroxyphenyl)-3-(4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
• 化学式: C₂₀H₁₅N₃O₃
• 分子量: 345.357
• InChiKey: DPSFKKBIIZTWDA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  98.2
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-溴-1-[(4-甲基苯基)磺酰基]-1H-吡咯并[2,3-B]吡啶 在 1,1'-双(二苯基膦)二茂铁 、 四(三苯基膦)钯 、 水 、 palladium diacetate 、 potassium carbonate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 potassium hydroxide 作用下， 以 甲醇 、 乙醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 5.17h， 生成 N,3-bis(3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
  参考文献：
  名称：

  Structural Optimization and Pharmacological Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) and CDC-like kinases (CLK) in Glioblastoma

  摘要：

  The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC50 <= 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells. Target engagement was confirmed with genetic knockdown and the cellular thermal shift assay. We demonstrate that DYRK1A's thermal stability in cells is increased upon compound treatment, confirming binding in cells. In summary, we present synthesis, structure activity relationship, and efficacy in glioblastoma-relevant models for a library of novel 7-azaindoles.

  DOI：

  10.1021/acs.jmedchem.6b01840

文献信息

• Structural Optimization and Pharmacological Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) and CDC-like kinases (CLK) in Glioblastoma
  作者：Qingqing Zhou、Athena F. Phoa、Ramzi H. Abbassi、Monira Hoque、Tristan A. Reekie、Josep S. Font、Renae M. Ryan、Brett W. Stringer、Bryan W. Day、Terrance G. Johns、Lenka Munoz、Michael Kassiou

  DOI：10.1021/acs.jmedchem.6b01840

  日期：2017.3.9

  The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC50 <= 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells. Target engagement was confirmed with genetic knockdown and the cellular thermal shift assay. We demonstrate that DYRK1A's thermal stability in cells is increased upon compound treatment, confirming binding in cells. In summary, we present synthesis, structure activity relationship, and efficacy in glioblastoma-relevant models for a library of novel 7-azaindoles.