ethyl 5-cyclopropyl-6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-5H-isoxazolo<5,4,3-de>quinoline-3-carboxylate | 151447-15-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: ethyl 5-cyclopropyl-6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-5H-isoxazolo<5,4,3-de>quinoline-3-carboxylate
• 英文别名: ethyl 7-cyclopropyl-10-(2,6-dimethylpyridin-4-yl)-9,11-difluoro-3-oxa-2,7-diazatricyclo[6.3.1.04,12]dodeca-1,4(12),5,8,10-pentaene-5-carboxylate
• CAS: 151447-15-3
• 化学式: C₂₂H₁₉F₂N₃O₃
• 分子量: 411.408
• InChiKey: XMCSOOYGIGWKKK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  68.5
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl 5-cyclopropyl-6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-5H-isoxazolo<5,4,3-de>quinoline-3-carboxylate 在 palladium on activated charcoal 氢气 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 25.0 ℃ 、344.73 kPa 条件下， 反应 3.0h， 以86%的产率得到5-Amino-1-cyclopropyl-7-(2,6-dimethyl-pyridin-4-yl)-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester
  参考文献：
  名称：

  Mammalian topoisomerase II inhibitory activity of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid and related derivatives

  摘要：

  1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 muM (VP-16; EC50 = 0.81 muM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.

  DOI：

  10.1021/jm00071a010
• 作为产物：
  描述：

  ethyl 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate 在 sodium azide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以40%的产率得到ethyl 5-cyclopropyl-6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-5H-isoxazolo<5,4,3-de>quinoline-3-carboxylate
  参考文献：
  名称：

  Mammalian topoisomerase II inhibitory activity of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid and related derivatives

  摘要：

  1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 muM (VP-16; EC50 = 0.81 muM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.

  DOI：

  10.1021/jm00071a010