4-phenoxy-2-(2H-tetrazol-5-yl)thieno[2,3-c]pyridine | 1078026-25-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-phenoxy-2-(2H-tetrazol-5-yl)thieno[2,3-c]pyridine
• CAS: 1078026-25-1
• 化学式: C₁₄H₉N₅OS
• 分子量: 295.324
• InChiKey: LQZKADWTXZGRQF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  21
• 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：
  105
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3,5-二溴-4-吡啶甲醛 在 sodium azide 、 2,2,6,6-四甲基-3,5-庚二酮 、 氯化铵 、 caesium carbonate 、 copper(l) chloride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.0h， 生成 4-phenoxy-2-(2H-tetrazol-5-yl)thieno[2,3-c]pyridine
  参考文献：
  名称：

  Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells

  摘要：

  Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-pi interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.

  DOI：

  10.1021/acsmedchemlett.5b00278

文献信息

• Discovery of thieno[2,3-c]pyridines as potent COT inhibitors
  作者：Dawn George、Michael Friedman、Hamish Allen、Maria Argiriadi、Claude Barberis、Agnieszka Bischoff、Anca Clabbers、Kevin Cusack、Richard Dixon、Shannon Fix-Stenzel、Thomas Gordon、Bernd Janssen、Yong Jia、Maria Moskey、Christopher Quinn、Jose-Andres Salmeron、Neil Wishart、Kevin Woller、Zhengtian Yu

  DOI：10.1016/j.bmcl.2008.08.037

  日期：2008.9

  Evaluation of hit chemotypes from high throughput screening identified a novel series of 2,4-disubstituted thieno[2,3-c]pyridines as COT kinase inhibitors. Structural modifications exploring SAR at the 2- and 4-positions resulting in inhibitors with improved enzyme potency and cellular activity are disclosed. (C) 2008 Elsevier Ltd. All rights reserved.
• Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells
  作者：Michael F. T. Koehler、Philippe Bergeron、Elizabeth M. Blackwood、Krista Bowman、Kevin R. Clark、Ron Firestein、James R. Kiefer、Klaus Maskos、Mark L. McCleland、Linda Orren、Laurent Salphati、Steve Schmidt、Elisabeth V. Schneider、Jiansheng Wu、Maureen H. Beresini

  DOI：10.1021/acsmedchemlett.5b00278

  日期：2016.3.10

  Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-pi interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.