(4'RS)-7',8'-dichloro-1'-oxo-1',2',4',9'-tetrahydrospiro[cyclohexane-1,3'-pyrido[3,4-b]indole]-4'-carbonitrile | 1353572-80-1

• 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: (4'RS)-7',8'-dichloro-1'-oxo-1',2',4',9'-tetrahydrospiro[cyclohexane-1,3'-pyrido[3,4-b]indole]-4'-carbonitrile
• 英文别名: 7,8-dichloro-1-oxospiro[4,9-dihydro-2H-pyrido[3,4-b]indole-3,1'-cyclohexane]-4-carbonitrile
• CAS: 1353572-80-1
• 化学式: C₁₇H₁₅Cl₂N₃O
• 分子量: 348.232
• InChiKey: FBEUQQMEAPWEGB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  23
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  68.7
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (4'RS)-7',8'-dichloro-1'-oxo-1',2',4',9'-tetrahydrospiro[cyclohexane-1,3'-pyrido[3,4-b]indole]-4'-carbonitrile 、 硫酸二甲酯 在 苄基三乙基氯化铵 、 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 12.0h， 以56%的产率得到(4'RS)-7',8'-dichloro-9'-methyl-1'-oxo-1',2',4',9'-tetrahydrospiro[cyclohexane-1,3'-pyrido[3,4-b]indole]-4'-carbonitrile
  参考文献：
  名称：

  7,8-Dichloro-1-oxo-β-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes

  摘要：

  Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-beta-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.

  DOI：

  10.1021/jm201286z
• 作为产物：
  描述：

  ethyl 6,7-dichloro-3-(cyanomethyl)-1H-indole-2-carboxylate 、 环己酮 在 氨 、 氯化铵 作用下， 反应 16.0h， 以19%的产率得到(4'RS)-7',8'-dichloro-1'-oxo-1',2',4',9'-tetrahydrospiro[cyclohexane-1,3'-pyrido[3,4-b]indole]-4'-carbonitrile
  参考文献：
  名称：

  7,8-Dichloro-1-oxo-β-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes

  摘要：

  Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-beta-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.

  DOI：

  10.1021/jm201286z

文献信息

• 7,8-Dichloro-1-oxo-β-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes
  作者：Kilian Huber、Laurent Brault、Oleg Fedorov、Christelle Gasser、Panagis Filippakopoulos、Alex N. Bullock、Doriano Fabbro、Jörg Trappe、Jürg Schwaller、Stefan Knapp、Franz Bracher

  DOI：10.1021/jm201286z

  日期：2012.1.12

  Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-beta-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.