2-amino-N-[4-(2-morpholin-4-yl-4-oxo-1,4-dihydroquinolin-8-yl)dibenzothiophen-1-yl]acetamide

• 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: 2-amino-N-[4-(2-morpholin-4-yl-4-oxo-1,4-dihydroquinolin-8-yl)dibenzothiophen-1-yl]acetamide
• 英文别名: 2-amino-N-[4-(2-morpholin-4-yl-4-oxo-1H-quinolin-8-yl)dibenzothiophen-1-yl]acetamide
• 化学式: C₂₇H₂₄N₄O₃S
• 分子量: 484.579
• InChiKey: QEVNJCJWYHKUEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  125
• 氢给体数：
  3
• 氢受体数：
  7

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 、 氨 、 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 、 正己烷 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 溶剂黄146 、 丙酮 为溶剂， 反应 103.0h， 生成 2-amino-N-[4-(2-morpholin-4-yl-4-oxo-1,4-dihydroquinolin-8-yl)dibenzothiophen-1-yl]acetamide
  参考文献：
  名称：

  DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype

  摘要：

  Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083-6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]-pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1 H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)(n) NR1 R-2, 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)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]-pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.

  DOI：

  10.1021/jm100608j

文献信息

• DNA-PK inhibitors
  申请人：Smith Cameron Murray Graeme

  公开号：US20060264427A1

  公开（公告）日：2006-11-23

  Compounds of formula I: wherein A, B and D are respectively selected from the group consisting of: (i) CH, NH, C; (ii) CH, N, N;and (iii) CH, O, C; the dotted lines represent two double bonds in the appropriate locations; and where Z is selected from S, O, C(═O), CH 2 and NH are disclosed for use in inhibiting DNA-PK.

  式I的化合物： 其中A、B和D分别从以下组中选择：(i) CH、NH、C；(ii) CH、N、N；和(iii) CH、O、C；虚线表示适当位置上的两个双键；Z从S、O、C(═O)、CH2和NH中选择，用于抑制DNA-PK。
• WO2006/109081
  申请人：——

  公开号：——

  公开（公告）日：——
• DNA-PK INHIBITORS
  申请人：Kudos Pharmaceuticals Ltd

  公开号：EP1869021A1

  公开（公告）日：2007-12-26
• USE OF DNA-PK INHIBITION TO SENSITISE ATM DEFICIENT CANCERS TO DNA-DAMAGING CANCER THERAPIES
  申请人：Smith Graeme Cameron Murray

  公开号：US20090035394A1

  公开（公告）日：2009-02-05

  This invention relates to the finding that inhibition of the catalytic subunit of DNA protein kinase (DNA-PKcs) increases the sensitivity of cancer cells that display an ATM deficient phenotype to DNA damaging therapies, such as irradiation or chemotherapy. Methods of treating cancers displaying an ATM deficient phenotype and methods of determining the susceptibility of a patient to such methods are provided.
• US7696203B2
  申请人：——

  公开号：US7696203B2

  公开（公告）日：2010-04-13