(Z)-ethyl 3-(2-amino-1-cyanovinyl)-6,7-dichloro-1-methyl-1H-indole-2-carboxylate

• 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: (Z)-ethyl 3-(2-amino-1-cyanovinyl)-6,7-dichloro-1-methyl-1H-indole-2-carboxylate
• 英文别名: Ethyl 3-(2-Amino-1-cyanoethenyl)-6,7-dichloro-1-methylindole-2-carboxylate；ethyl 3-[(Z)-2-amino-1-cyanoethenyl]-6,7-dichloro-1-methylindole-2-carboxylate
• 化学式: C₁₅H₁₃Cl₂N₃O₂
• 分子量: 338.193
• InChiKey: CXJCGSPAPOTTSF-SOFGYWHQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  81
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  ethyl 6,7-dichloro-3-[1-cyano-2-(dimethylamino)vinyl]-1-methyl-1H-indole-2-carboxylate 在 硫酸 、 ammonium acetate 、 溶剂黄146 作用下， 反应 0.25h， 生成 KH-CB19 、 (Z)-ethyl 3-(2-amino-1-cyanovinyl)-6,7-dichloro-1-methyl-1H-indole-2-carboxylate
  参考文献：
  名称：

  Specific CLK Inhibitors from a Novel Chemotype for Regulation of Alternative Splicing

  摘要：

  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).

  DOI：

  10.1016/j.chembiol.2010.11.009

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).