(E)-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one | 1448454-16-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (E)-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one
• 英文别名: (E)-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)-1-((2-(trimetnylsilyl)ethoxy)methyl)indolin-2-one；(3E)-3-[[3-[(E)-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]ethenyl]-1-(2-trimethylsilylethoxymethyl)indazol-6-yl]methylidene]-1H-indol-2-one
• CAS: 1448454-16-7
• 化学式: C₃₄H₄₀N₆O₂Si
• 分子量: 592.816
• InChiKey: YSPUYADWYZOCNI-ZWWBNRKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.16
• 重原子数：
  43
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  75.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (E)-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 在 盐酸 、 三氟化硼乙醚 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 7.0h， 生成 (E)-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one dihydrochloride
  参考文献：
  名称：

  The Discovery of PLK4 Inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents

  摘要：

  The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.

  DOI：

  10.1021/jm400380m
• 作为产物：
  描述：

  2-(4-甲基哌嗪-1-基)吡啶-5-硼酸频那醇酯 在 哌啶 、 palladium diacetate 、 N,N-二异丙基乙胺 、 三(邻甲基苯基)磷 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙腈 为溶剂， 反应 30.17h， 生成 (E)-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 、 (Z)-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one
  参考文献：
  名称：

  The Discovery of PLK4 Inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents

  摘要：

  The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.

  DOI：

  10.1021/jm400380m

文献信息

• The Discovery of PLK4 Inhibitors: (<i>E</i>)-3-((1<i>H</i>-Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents
  作者：Radoslaw Laufer、Bryan Forrest、Sze-Wan Li、Yong Liu、Peter Sampson、Louise Edwards、Yunhui Lang、Donald E. Awrey、Guodong Mao、Olga Plotnikova、Genie Leung、Richard Hodgson、Irina Beletskaya、Jacqueline M. Mason、Xunyi Luo、Xin Wei、Yi Yao、Miklos Feher、Fuqiang Ban、Reza Kiarash、Erin Green、Tak W. Mak、Guohua Pan、Henry W. Pauls

  DOI：10.1021/jm400380m

  日期：2013.8.8

  The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.