ethyl 4-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de][1,7]-naphthyridin-1-yl)butanoate | 1428122-99-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: ethyl 4-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de][1,7]-naphthyridin-1-yl)butanoate
• 英文别名: Ethyl 4-(10-oxo-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-2-yl)butanoate；ethyl 4-(10-oxo-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-2-yl)butanoate
• CAS: 1428122-99-9
• 化学式: C₁₇H₂₂N₂O₃
• 分子量: 302.373
• InChiKey: MCBLWKNNDFTFRU-UHFFFAOYSA-N

物化性质

• 沸点：
  517.8±50.0 °C(predicted)
• 密度：
  1.169±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 4-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de][1,7]-naphthyridin-1-yl)butanoate 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 N-[2-[4-(4-methoxyphenyl)piperazin-1-yl]-2-oxoethyl]-4-(10-oxo-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-2-yl)butanamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors

  摘要：

  A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

  DOI：

  10.1021/jm301825t
• 作为产物：
  描述：

  4,6,7,8-四氢-1H,3H-喹啉-2,5-二酮 在 sodium azide 、 potassium carbonate 、 sodium iodide 作用下， 以 甲烷磺酸 、 二氯甲烷 、 乙腈 为溶剂， 反应 48.0h， 生成 ethyl 4-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de][1,7]-naphthyridin-1-yl)butanoate
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors

  摘要：

  A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

  DOI：

  10.1021/jm301825t