ethyl 6,7-dichloro-3-(cyanomethyl)-1-methyl-1H-indole-2-carboxylate | 1264299-44-6

• 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: ethyl 6,7-dichloro-3-(cyanomethyl)-1-methyl-1H-indole-2-carboxylate
• 英文别名: ethyl 3-(cyanomethyl)-6,7-dichloro-1-methyl-1H-indole-2-carboxylate；Ethyl 6,7-dichloro-3-(cyanomethyl)-1-methylindole-2-carboxylate；ethyl 6,7-dichloro-3-(cyanomethyl)-1-methylindole-2-carboxylate
• CAS: 1264299-44-6
• 化学式: C₁₄H₁₂Cl₂N₂O₂
• 分子量: 311.167
• InChiKey: NNNBKCSWIMARKO-UHFFFAOYSA-N

物化性质

• 沸点：
  502.8±50.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  55
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl 6,7-dichloro-3-(cyanomethyl)-1-methyl-1H-indole-2-carboxylate 在 tetra-N-butylammonium borohydride 、 氨 、 氯化铵 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 25.0h， 生成 (4RS)-N-[(7,8-dichloro-3,3,9-trimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-4-yl)methyl]acetamide
  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 、 碘甲烷 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以80%的产率得到ethyl 6,7-dichloro-3-(cyanomethyl)-1-methyl-1H-indole-2-carboxylate
  参考文献：
  名称：

  多元合成3-取代的4-氰基1,2,3,4-四氢-1-氧代-β-咔啉

  摘要：

  在旨在合成具有更有利的溶解性的细胞毒性β-咔啉生物碱bauerine C的类似物的项目中，通过用氨处理3-（氰基甲基）吲哚-2-羧酸乙酯来制备3-氨基类似物。在将醛或酮加至反应混合物中后，通过一锅缩合反应获得3-取代的4-氰基-1,2,3,4-四氢-1-氧代-β-咔啉。当使用环状酮时，该方法可以方便地合成四环螺化合物。 β-咔啉-环化-多组分反应-吲哚-内酰胺

  DOI：

  10.1055/s-0030-1258282

文献信息

• Specific CLK Inhibitors from a Novel Chemotype for Regulation of Alternative Splicing
  作者：Oleg Fedorov、Kilian Huber、Andreas Eisenreich、Panagis Filippakopoulos、Oliver King、Alex N. Bullock、Damian Szklarczyk、Lars J. Jensen、Doriano Fabbro、Jörg Trappe、Ursula Rauch、Franz Bracher、Stefan Knapp

  DOI：10.1016/j.chembiol.2010.11.009

  日期：2011.1

  There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix αC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19 effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF).
• A Versatile Synthesis of 3-Substituted 4-Cyano-1,2,3,4-tetrahydro-1-oxo-β-carbolines
  作者：Franz Bracher、Kilian Huber、Oliver Kast

  DOI：10.1055/s-0030-1258282

  日期：2010.11

  -2-carboxylate with ammonia. Upon addition of aldehydes or ketones to the reaction mixture, 3-substituted 4-cyano-1,2,3,4-tetrahydro-1-oxo-β-carbolines were obtained in a one-pot condensation. When cyclic ketones are used, the procedure allows a convenient synthesis of tetracyclic spiro compounds. β-carbolines - cyclizations - multicomponent reactions - indoles - lactams

  在旨在合成具有更有利的溶解性的细胞毒性β-咔啉生物碱bauerine C的类似物的项目中，通过用氨处理3-（氰基甲基）吲哚-2-羧酸乙酯来制备3-氨基类似物。在将醛或酮加至反应混合物中后，通过一锅缩合反应获得3-取代的4-氰基-1,2,3,4-四氢-1-氧代-β-咔啉。当使用环状酮时，该方法可以方便地合成四环螺化合物。 β-咔啉-环化-多组分反应-吲哚-内酰胺
• 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.