ethyl 7-(2,6-dimethyl-4-pyridinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate | 151447-08-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: ethyl 7-(2,6-dimethyl-4-pyridinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate
• 英文别名: ethyl 7-(2,6-dimethylpyridin-4-yl)-6,8-difluoro-4-oxo-1H-quinoline-3-carboxylate
• CAS: 151447-08-4
• 化学式: C₁₉H₁₆F₂N₂O₃
• 分子量: 358.344
• InChiKey: LFAOOHRFSIGDAC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.66
• 重原子数：
  26.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  72.05
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  ethyl 7-(2,6-dimethyl-4-pyridinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 在 sodium hydroxide 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.5h， 生成 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid
  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：

  diethyl <<<3-(2,6-dimethyl-4-pyridinyl)-2,4-difluorophenyl>amino>methylene>propanedioate 以 二苯醚 为溶剂， 反应 0.33h， 以70%的产率得到ethyl 7-(2,6-dimethyl-4-pyridinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-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