6-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-2,6-diazatricyclo[7.3.1.05,13]trideca-1(12),9(13),10-trien-3-one | 1428123-25-4

• 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: 6-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-2,6-diazatricyclo[7.3.1.05,13]trideca-1(12),9(13),10-trien-3-one
• CAS: 1428123-25-4
• 化学式: C₂₇H₂₁FN₄O₃
• 分子量: 468.487
• InChiKey: AAUSESQBFIRQBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  35
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  90.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4,6,7,8-四氢-1H,3H-喹啉-2,5-二酮 在 sodium azide 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 甲烷磺酸 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 6-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-2,6-diazatricyclo[7.3.1.05,13]trideca-1(12),9(13),10-trien-3-one
  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