N-[2-[4-(2-fluorophenyl)piperazin-1-yl]-2-oxoethyl]-3-(10-oxo-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-2-yl)propanamide | 1428123-07-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: N-[2-[4-(2-fluorophenyl)piperazin-1-yl]-2-oxoethyl]-3-(10-oxo-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-2-yl)propanamide
• CAS: 1428123-07-2
• 化学式: C₂₆H₃₀FN₅O₃
• 分子量: 479.554
• InChiKey: SIMOJUUGNCRQQM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  85
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(2-氟苯基)哌嗪 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 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 N-[2-[4-(2-fluorophenyl)piperazin-1-yl]-2-oxoethyl]-3-(10-oxo-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-2-yl)propanamide
  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

文献信息

• Design, Synthesis, and Biological Evaluation of a Series of Benzo[<i>de</i>][1,7]naphthyridin-7(8<i>H</i>)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors
  作者：Na Ye、Chuan-Huizi Chen、TianTian Chen、Zilan Song、Jin-Xue He、Xia-Juan Huan、Shan-Shan Song、Qiufeng Liu、Yi Chen、Jian Ding、Yechun Xu、Ze-Hong Miao、Ao Zhang

  DOI：10.1021/jm301825t

  日期：2013.4.11

  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.