6,7-difluoro-2,3-dimethylquinazolin-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: 6,7-difluoro-2,3-dimethylquinazolin-4(3H)-one
• 英文别名: 6,7-Difluoro-2,3-dimethylquinazolin-4-one；6,7-difluoro-2,3-dimethylquinazolin-4-one
• 化学式: C₁₀H₈F₂N₂O
• 分子量: 210.183
• InChiKey: HLJGNDGAZUNODS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  32.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6,7-difluoro-2,3-dimethylquinazolin-4(3H)-one 在 三甲基氯硅烷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 (E)-7-((2-(diethylamino)ethyl)amino)-6-fluoro-2-(4-isopropylstyryl)-3-methylquinazolin-4(3H)-one
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors

  摘要：

  DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.

  DOI：

  10.1021/acs.jmedchem.0c00917
• 作为产物：
  描述：

  2-氨基-4,5-二氟苯甲酸 反应 1.5h， 生成 6,7-difluoro-2,3-dimethylquinazolin-4(3H)-one
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors

  摘要：

  DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.

  DOI：

  10.1021/acs.jmedchem.0c00917

文献信息

• Discovery of Novel Schizocommunin Derivatives as Telomeric G-Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response
  作者：Tong Che、Shuo-Bin Chen、Jia-Li Tu、Bo Wang、Yu-Qing Wang、Yan Zhang、Jing Wang、Zeng-Qing Wang、Ze-Peng Zhang、Tian-Miao Ou、Yong Zhao、Jia-Heng Tan、Zhi-Shu Huang

  DOI：10.1021/acs.jmedchem.7b01615

  日期：2018.4.26

  Telomeric G-quadruplex targeting and telomere maintenance interference are emerging as attractive strategies for anticancer therapies. Here, a novel molecular scaffold is explored for telomeric G-quadruplex targeting. A series of novel schizocommunin derivatives was designed and synthesized as potential telomeric G-quadruplex ligands. The interaction of telomeric G-quadruplex DNA with the derivatives

  端粒G-四链体靶向和端粒维持干扰正在作为抗癌治疗的有吸引力的策略出现。在这里，一种新型的分子支架被研究用于端粒G-四链体靶向。设计和合成了一系列新型的schizocommunin衍生物，作为潜在的端粒G-四链体配体。通过生物物理分析探索端粒G-四链体DNA与衍生物的相互作用。通过甲基噻唑基四唑鎓（MTT）测定法评估了衍生物对癌细胞系的细胞毒性。在衍生物中，化合物16显示出对端粒G-四链体DNA的稳定能力和对癌细胞系的良好细胞毒性。进一步的细胞实验表明16可能会诱导细胞中端粒G-四链体的形成，在端粒处引发DNA损伤反应，并导致端粒功能障碍。这些作用最终引起了p53介导的细胞周期停滞和凋亡，并在小鼠异种移植模型中抑制了肿瘤的生长。我们的工作为端粒G-四链体配体的发展提供了一种新型的支架。
• 一种Schizocommunin衍生物及其制备方法和 应用
  申请人：中山大学

  公开号：CN107540662B

  公开（公告）日：2020-04-24

  本发明属于药物化学领域，具体涉及一种Schizocommunin衍生物及其制备方法和应用。所述Schizocommunin衍生物的结构式如下：式中：R1、R3为氢或氟原子，R2为N,N‑二甲基丙二胺基、N,N‑二乙基乙二胺基、五元或六元杂环基，R4为氢原子、五元或六元杂环基，R5为氢原子、五元或六元杂环基、R6为氢原子或甲基。本发明提供的Schizocommunin衍生物与富含鸟嘌呤的端粒DNA具有很强的结合和稳定能力，表现出显著的抗癌作用，进一步实验表明，本发明提供的Schizocommunin衍生物对多种癌细胞株具有显著的抑制作用，在制备抗肿瘤药物上有着广阔的应用空间。
• PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS
  申请人：Gilead Sciences, Inc.

  公开号：US20140371246A1

  公开（公告）日：2014-12-18

  The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (I), or pharmaceutically acceptable salts or isomers thereof, in which n, m, R 1 , R 2 , R 4 , and R 3 are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms, such as PI3Kδ. The present disclosure further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts or isomers thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms, such as PI3Kδ.

  本公开提供了式（I）的磷脂酰肌醇3-激酶（PI3K）抑制剂，或其药用盐或异构体，其中n、m、R1、R2、R4和R3如本文所定义。这些化合物可用于治疗由一个或多个PI3K同工酶介导的疾病，如PI3Kδ。本公开还提供了包括式（I）的化合物、药用盐或异构体的药物组合物，以及使用这些化合物和组合物治疗由一个或多个PI3K同工酶介导的疾病，如PI3Kδ的方法。
• US9029384B2
  申请人：——

  公开号：US9029384B2

  公开（公告）日：2015-05-12
• US9221795B2
  申请人：——

  公开号：US9221795B2

  公开（公告）日：2015-12-29