3-morpholino-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)-dibenzo[b,d]thiophen-1-yl)propanamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻吩类
• 英文名称: 3-morpholino-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)-dibenzo[b,d]thiophen-1-yl)propanamide
• 英文别名: 3-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxochromen-8-yl)dibenzothiophen-1-yl]propanamide
• 化学式: C₃₂H₃₁N₃O₅S
• 分子量: 569.681
• InChiKey: FXKRFWSVCZPMBS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  二苯并噻吩 在 1,1'-双(二苯基膦)二茂铁 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 正丁基锂 、 硝酸 、 potassium acetate 、 吡啶盐酸盐 、 potassium carbonate 、 caesium carbonate 、 溶剂黄146 、 三乙胺 、 锌 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 丙酮 为溶剂， 反应 34.0h， 生成 3-morpholino-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)-dibenzo[b,d]thiophen-1-yl)propanamide
  参考文献：
  名称：

  1-Substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones Endowed with Dual DNA-PK/PI3-K Inhibitory Activity

  摘要：

  Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 +/- 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH2)(n)(NRR2)-R-1, where n = 1 or 2 and the moiety (RRN)-R-1-N-2 was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethyl-piperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)-dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC50 = 5.0 +/- 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.

  DOI：

  10.1021/jm400915j

文献信息

• [EN] DNA-PK INHIBITORS<br/>[FR] INHIBITEURS D'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2006032869A1

  公开（公告）日：2006-03-30

  A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, C3-20 heterocyclyl group, or C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; Q is -NH-C(=O)- or -O-; Y is an optionally substituted C1-5 alkylene group; X is selected from SR3 or NR4R5, wherein, R3, or R4 and R5 are independently selected from hydrogen, optionally substituted C1-7 alkyl, C5-20 aryl, or C3-20 heterocyclyl groups, or R4 and R5 may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; if Q is -O-, X is additionally selected from -C(=O)-NR6R7, wherein R6 and R7 are independently selected from hydrogen, optionally substituted C1-7 alkyl, C5-20 aryl, or C3-20 heterocyclyl groups, or R6 and R7 may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and if Q is -NH-C(=O)-, -Y-X may additionally be selected from C1-7 alkyl.

  化合物I的分子式为：及其异构体、盐、溶剂和化学保护形式、以及其前药，其中：R1和R2独立选择氢、可选取代的C1-7烷基、C3-20杂环基或C5-20芳基，或者与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；Q为-NH-C（=O）-或-O-；Y为可选取代的C1-5烷基；X选自SR3或NR4R5，其中R3，或R4和R5独立选择氢、可选取代的C1-7烷基、C5-20芳基或C3-20杂环基，或者R4和R5可以与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；如果Q为-O-，X还被选自-C（=O）-NR6R7，其中R6和R7独立选择氢、可选取代的C1-7烷基、C5-20芳基或C3-20杂环基，或者R6和R7可以与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；如果Q为-NH-C（=O）-，-Y-X还可以被选自C1-7烷基。