1-benzyl-1,2,3,8,9,9a-hexahydro-7H-benzo[de]-1,7-naphthyridin-7-one

• 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: 1-benzyl-1,2,3,8,9,9a-hexahydro-7H-benzo[de]-1,7-naphthyridin-7-one
• 英文别名: 2-Benzyl-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-10-one
• 化学式: C₁₈H₁₈N₂O
• 分子量: 278.354
• InChiKey: AKZIIMCENGVIGG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  32.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-benzyl-1,2,3,8,9,9a-hexahydro-7H-benzo[de]-1,7-naphthyridin-7-one 在 lithium aluminium tetrahydride 、 palladium 10% on activated carbon 、 氢气 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、10.34 kPa 条件下， 反应 32.0h， 生成 4-[[3-(2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-triene-11-carbonyl)-4-fluorophenyl]methyl]-2H-phthalazin-1-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
• 作为产物：
  描述：

  4,6,7,8-四氢-1H,3H-喹啉-2,5-二酮 在 sodium azide 、 甲烷磺酸 、 potassium carbonate 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 2.0h， 生成 1-benzyl-1,2,3,8,9,9a-hexahydro-7H-benzo[de]-1,7-naphthyridin-7-one
  参考文献：
  名称：

  一类哒嗪酮类化合物及其制备方法和用途

  摘要：

  本发明涉及一类如下通式I表示的哒嗪酮类化合物、其制备方法及其在制备预防或治疗与核糖多聚ADP‑核糖聚合酶（PARP）相关的疾病的药物中的用途。

  公开号：

  CN103833756B

文献信息

• 一类哒嗪酮类化合物及其制备方法和用途
  申请人：中国科学院上海药物研究所

  公开号：CN103833756B

  公开（公告）日：2016-12-21

  本发明涉及一类如下通式I表示的哒嗪酮类化合物、其制备方法及其在制备预防或治疗与核糖多聚ADP‑核糖聚合酶（PARP）相关的疾病的药物中的用途。
• Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)
  作者：Caterina Torrisi、Monica Bisbocci、Raffaele Ingenito、Jesus M. Ontoria、Michael Rowley、Carsten Schultz-Fademrecht、Carlo Toniatti、Philip Jones

  DOI：10.1016/j.bmcl.2009.12.002

  日期：2010.1

  A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties. (C) 2009 Elsevier Ltd. All rights reserved.
• WO2008/1134
  申请人：——

  公开号：——

  公开（公告）日：——
• 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.