7,8-dimethyl-2-((pyrimidin-2-ylthio)methyl)quinazolin-4(3H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 7,8-dimethyl-2-((pyrimidin-2-ylthio)methyl)quinazolin-4(3H)-one
• 英文别名: 7,8-dimethyl-2-(pyrimidin-2-ylsulfanylmethyl)-3~{H}-quinazolin-4-one；7,8-dimethyl-2-(pyrimidin-2-ylsulfanylmethyl)-3H-quinazolin-4-one
• 化学式: C₁₅H₁₄N₄OS
• 分子量: 298.368
• InChiKey: NHFMMPLQVIZDPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  92.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  methyl 2-amino-3,4-dimethylbenzoate 在 盐酸 、 sodium hydride 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.66h， 生成 7,8-dimethyl-2-((pyrimidin-2-ylthio)methyl)quinazolin-4(3H)-one
  参考文献：
  名称：

  A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity

  摘要：

  Poly-ADP-ribose polymerases (PARPs1-16) play pivotal roles in diverse cellular processes. PARPs that catalyze poly-ADP-ribosylation (PARylation) are the best characterized PARP family members because of the availability of potent and selective inhibitors for these PARPs. There has been comparatively little success in developing selective small-molecule inhibitors of PARPs that catalyze mono-ADP-ribosylation (MARylation), limiting our understanding of the cellular role of MARylation. Here we describe the structure-guided design of inhibitors of PARPs that catalyze MARylation. The most selective analog, ITK7, potently inhibits the MARylation activity of PARP11, a nuclear envelope-localized PARP. ITK7 is greater than 200-fold selective over other PARP family members. Using live-cell imaging, we show that ITK7 causes PARP11 to dissociate from the nuclear envelope. These results suggest that the cellular localization of PARP11 is regulated by its catalytic activity.

  DOI：

  10.1016/j.chembiol.2018.09.011

文献信息

• [EN] PARP INHIBITORS FOR TREATING CANCER AND ASTHMA<br/>[FR] INHIBITEURS DE PARP POUR LE TRAITEMENT DU CANCER ET DE L'ASTHME
  申请人：UNIV OREGON HEALTH & SCIENCE

  公开号：WO2020046753A1

  公开（公告）日：2020-03-05

  Provided are substituted 8-methylquinazolin-4(3H)-one compounds useful as PARP inhibitors for the treatment of cancer and asthma, as well as pharmaceutical compositions comprising them and methods for their synthesis.

  提供了替代8-甲基喹唑啉-4(3H)-酮化合物，可用作PARP抑制剂，用于治疗癌症和哮喘，以及包含它们的药物组合物和合成方法。
• PARP INHIBITORS FOR TREATING CANCER AND ASTHMA
  申请人：Oregon Health & Science University

  公开号：EP3843726A1

  公开（公告）日：2021-07-07
• A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity
  作者：Ilsa T. Kirby、Ana Kojic、Moriah R. Arnold、Ann-Gerd Thorsell、Tobias Karlberg、Anke Vermehren-Schmaedick、Raashi Sreenivasan、Carsten Schultz、Herwig Schüler、Michael S. Cohen

  DOI：10.1016/j.chembiol.2018.09.011

  日期：2018.12

  Poly-ADP-ribose polymerases (PARPs1-16) play pivotal roles in diverse cellular processes. PARPs that catalyze poly-ADP-ribosylation (PARylation) are the best characterized PARP family members because of the availability of potent and selective inhibitors for these PARPs. There has been comparatively little success in developing selective small-molecule inhibitors of PARPs that catalyze mono-ADP-ribosylation (MARylation), limiting our understanding of the cellular role of MARylation. Here we describe the structure-guided design of inhibitors of PARPs that catalyze MARylation. The most selective analog, ITK7, potently inhibits the MARylation activity of PARP11, a nuclear envelope-localized PARP. ITK7 is greater than 200-fold selective over other PARP family members. Using live-cell imaging, we show that ITK7 causes PARP11 to dissociate from the nuclear envelope. These results suggest that the cellular localization of PARP11 is regulated by its catalytic activity.