2-morpholin-4-yl-8-(6',7',8',9'-tetrahydrodibenzothiophen-4'-yl)chromen-4-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 2-morpholin-4-yl-8-(6',7',8',9'-tetrahydrodibenzothiophen-4'-yl)chromen-4-one
• 英文别名: 2-Morpholin-4-yl-8-(6,7,8,9-tetrahydro-dibenzothiophen-4-yl)-chromen-4-one；2-morpholin-4-yl-8-(6,7,8,9-tetrahydrodibenzothiophen-4-yl)chromen-4-one
• 化学式: C₂₅H₂₃NO₃S
• 分子量: 417.529
• InChiKey: LLPTWYAVHXNSIY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  67
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-乙酰基吗啉 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 三氟甲磺酸酐 、 caesium carbonate 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 94.0h， 生成 2-morpholin-4-yl-8-(6',7',8',9'-tetrahydrodibenzothiophen-4'-yl)chromen-4-one
  参考文献：
  名称：

  Discovery of Potent Chromen-4-one Inhibitors of the DNA-Dependent Protein Kinase (DNA-PK) Using a Small-Molecule Library Approach

  摘要：

  Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxysubstituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNAPK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32{38} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 mu M. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.

  DOI：

  10.1021/jm050444b

文献信息

• DNA-PKCS MODULATES ENERGY REGULATION AND BRAIN FUNCTION
  申请人：Chung Jay Hang

  公开号：US20100130597A1

  公开（公告）日：2010-05-27

  The invention relates to new functions of the DNA-PKcs gene product in energy metabolism, brain function and physical fitness.
• [EN] DNA-PKCS MODULATES ENERGY REGULATION AND BRAIN FUNCTION<br/>[FR] MODULATION DE LA RÉGULATION D'ÉNERGIE ET DE LA FONCTION CÉRÉBRALE PAR ADN-PKCS
  申请人：US GOV NAT INST HEALTH

  公开号：WO2009008991A2

  公开（公告）日：2009-01-15

  The invention relates to new functions of the DNA-PKcs gene product in energy metabolism, brain function and physical fitness.
• Discovery of Potent Chromen-4-one Inhibitors of the DNA-Dependent Protein Kinase (DNA-PK) Using a Small-Molecule Library Approach
  作者：Ian R. Hardcastle、Xiaoling Cockcroft、Nicola J. Curtin、Marine Desage El-Murr、Justin J. J. Leahy、Martin Stockley、Bernard T. Golding、Laurent Rigoreau、Caroline Richardson、Graeme C. M. Smith、Roger J. Griffin

  DOI：10.1021/jm050444b

  日期：2005.12.1

  Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxysubstituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 3238}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 3226}) were excellent inhibitors (IC50 vs DNAPK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 3238} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 mu M. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.