2-(4-hydroxy-3,5-dimethoxyphenyl)quinazolin-4(3H)-one | 1427578-69-5

• 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: 2-(4-hydroxy-3,5-dimethoxyphenyl)quinazolin-4(3H)-one
• 英文别名: 2-(4-hydroxy-3,5-dimethoxyphenyl)-3H-quinazolin-4-one
• CAS: 1427578-69-5
• 化学式: C₁₆H₁₄N₂O₄
• 分子量: 298.298
• InChiKey: BHRDTEFAJMKLHB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  80.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(4-hydroxy-3,5-dimethoxyphenyl)quinazolin-4(3H)-one 在 三甲基铵三氧化硫共聚物 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 0.5h， 生成 sodium;[2,6-dimethoxy-4-(4-oxo-3H-quinazolin-2-yl)phenyl] sulfate
  参考文献：
  名称：

  Discovery of Allosteric Modulators of Factor XIa by Targeting Hydrophobic Domains Adjacent to Its Heparin-Binding Site

  摘要：

  To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the V-max of substrate hydrolysis without influencing the K-M. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs.

  DOI：

  10.1021/jm301757v
• 作为产物：
  描述：

  2-氨基苯甲酰胺 、 丁香醛 以 二甲基亚砜 为溶剂， 以33%的产率得到2-(4-hydroxy-3,5-dimethoxyphenyl)quinazolin-4(3H)-one
  参考文献：
  名称：

  Synthesized 2-Trifluoromethylquinazolines and Quinazolinones Protect BV2 and N2a Cells against LPS- and H2O2-induced Cytotoxicity

  摘要：

  背景：微胶质细胞与神经炎症有关，对神经退行性疾病的发病起着关键作用。据报道，一些喹唑啉和喹唑啉酮具有抗炎性能。然而，某些喹唑啉衍生物的药理特性仍未知。 目标：研究一系列合成的2-三氟甲基喹唑啉（2、4和5）和喹唑啉酮（6-8）在脂多糖（LPS）-小鼠微胶质细胞（BV2）和过氧化氢（H₂O₂）-小鼠神经母细胞瘤-2a（N2a）细胞中的抗氧化、细胞毒性和保护作用。 方法：用ABTS和DPPH测定合成化合物的抗氧化活性。通过MTS法测定BV2和N2a细胞的细胞毒性活性。定量测定LPS诱导的BV2微胶质细胞中的一氧化氮（NO）产生量。 结果：化合物8表现出最高的ABTS和DPPH清除活性，ABTS清除率为87.7%，DPPH抑制率为54.2%。所有化合物在5和50 μg/mL浓度下对BV2和N2a细胞均无细胞毒性。在LPS诱导的BV2和H₂O₂诱导的N2a细胞中，表现出最高保护作用的化合物分别为5和7。除4外，所有测试化合物在50 μg/mL浓度下也减少了NO的产生。喹唑啉酮系列6-8表现出最高的NO减少百分比，范围在38%到60%之间。化合物5和8具有平衡的抗氧化和保护性能，对LPS和H₂O₂诱导的细胞死亡具有潜在的抗炎和神经保护作用。 结论：化合物5和7能够以低浓度（5 μg/mL）保护BV2和N2a细胞免受LPS和H₂ O₂的毒性影响。化合物6-8显示出在BV2细胞中强效减少NO产生的作用。

  DOI：

  10.2174/1573406416666191218095635

文献信息

• [EN] ALLOSTERIC MODULATORS OF FACTOR XIa AS ANTICOAGULANT AGENTS<br/>[FR] MODULATEURS ALLOSTÉRIQUES DE FACTEUR XIA EN TANT QU'AGENTS ANTICOAGULANTS
  申请人：UNIV VIRGINIA COMMONWEALTH

  公开号：WO2014075045A1

  公开（公告）日：2014-05-15

  Compounds which allosterically modulate and/or inhibit factor XIa activity are provided, as are methods of their use. These compounds include i) sulfated gallolyl glucosides, ii) sulfated quinazolinones, and iii) sulfated inositol analogs. The compounds used as anticoagulant agents.

  提供了能够以别构调节和/或抑制XIa因子活性的化合物，以及它们的使用方法。这些化合物包括i) 硫酸酯化没食子醇葡萄糖苷，ii) 硫酸酯化喹唑啉酮，和iii) 硫酸酯化肌醇类似物。这些化合物被用作抗凝剂。
• Synthesized 2-Trifluoromethylquinazolines and Quinazolinones Protect BV2 and N2a Cells against LPS- and H2O2-induced Cytotoxicity
  作者：Neeranjini Nallathamby、Chia-Wei Phan、Matej Sova、Luciano Saso、Vikineswary Sabaratnam

  DOI：10.2174/1573406416666191218095635

  日期：2021.7

  Microglia are associated with neuroinflammation, which play a key role in the pathogenesis of neurodegenerative diseases. It has been reported that some quinazolines and quinazolinones possess anti-inflammatory properties. However, the pharmacological properties of certain quinazoline derivatives are still unknown.

  The antioxidant, cytotoxic, and protective effects of a series of synthesized 2- trifluoromethylquinazolines (2, 4, and 5) and quinazolinones (6-8) in lipopolysaccharide (LPS)- murine microglia (BV2) and hydrogen peroxide (H₂O₂)-mouse neuroblastoma-2a (N2a) cells were investigated.

  The antioxidant activity of synthesized compounds was evaluated with ABTS and DPPH assays. The cytotoxic activities were determined by MTS assay in BV2 and N2a cells. The production of nitric oxide (NO) in LPS-induced BV2 microglia cells was quantified.

  The highest ABTS and DPPH scavenging activities were observed for compound 8 with 87.7% of ABTS scavenge percentage and 54.2% DPPH inhibition. All compounds were noncytotoxic in BV2 and N2a cells at 5 and 50 μg/mL. The compounds which showed the highest protective effects in LPS-induced BV2 and H₂O₂-induced N2a cells were 5 and 7. All tested compounds, except 4, also reduced NO production at concentrations of 50 μg/mL. The quinazolinone series 6-8 exhibited the highest percentage of NO reduction, ranging from 38 to 60%. Compounds 5 and 8 possess balanced antioxidant and protective properties against LPS- and H₂O₂-induced cell death, thus showing great potential to be developed into anti-inflammatory and neuroprotective agents.

  Compounds 5 and 7 were able to protect the BV2 and N2a cells against LPS and H₂O₂ toxicity, respectively, at a low concentration (5 μg/mL). Compounds 6-8 showed potent reduction of NO production in BV2 cells.

  背景：微胶质细胞与神经炎症有关，对神经退行性疾病的发病起着关键作用。据报道，一些喹唑啉和喹唑啉酮具有抗炎性能。然而，某些喹唑啉衍生物的药理特性仍未知。 目标：研究一系列合成的2-三氟甲基喹唑啉（2、4和5）和喹唑啉酮（6-8）在脂多糖（LPS）-小鼠微胶质细胞（BV2）和过氧化氢（H₂O₂）-小鼠神经母细胞瘤-2a（N2a）细胞中的抗氧化、细胞毒性和保护作用。 方法：用ABTS和DPPH测定合成化合物的抗氧化活性。通过MTS法测定BV2和N2a细胞的细胞毒性活性。定量测定LPS诱导的BV2微胶质细胞中的一氧化氮（NO）产生量。 结果：化合物8表现出最高的ABTS和DPPH清除活性，ABTS清除率为87.7%，DPPH抑制率为54.2%。所有化合物在5和50 μg/mL浓度下对BV2和N2a细胞均无细胞毒性。在LPS诱导的BV2和H₂O₂诱导的N2a细胞中，表现出最高保护作用的化合物分别为5和7。除4外，所有测试化合物在50 μg/mL浓度下也减少了NO的产生。喹唑啉酮系列6-8表现出最高的NO减少百分比，范围在38%到60%之间。化合物5和8具有平衡的抗氧化和保护性能，对LPS和H₂O₂诱导的细胞死亡具有潜在的抗炎和神经保护作用。 结论：化合物5和7能够以低浓度（5 μg/mL）保护BV2和N2a细胞免受LPS和H₂ O₂的毒性影响。化合物6-8显示出在BV2细胞中强效减少NO产生的作用。
• ALLOSTERIC MODULATORS OF FACTOR XIa AS ANTICOAGULANT AGENTS
  申请人：VIRGINIA COMMONWEALTH UNIVERSITY

  公开号：US20160311842A1

  公开（公告）日：2016-10-27

  Compounds which allosterically modulate and/or inhibit factor XIa activity are provided, as are methods of their use. These compounds include i) sulfated gallolyl glucosides, ii) sulfated quinazolinones, and iii) sulfated inositol analogs. The compounds used as anticoagulant agents.
• US9758459B2
  申请人：——

  公开号：US9758459B2

  公开（公告）日：2017-09-12
• Discovery of Novel Dual-Target Inhibitor of Bromodomain-Containing Protein 4/Casein Kinase 2 Inducing Apoptosis and Autophagy-Associated Cell Death for Triple-Negative Breast Cancer Therapy
  作者：Jifa Zhang、Pan Tang、Ling Zou、Jin Zhang、Juncheng Chen、Chengcan Yang、Gu He、Bo Liu、Jie Liu、Cheng-Ming Chiang、Guan Wang、Tinghong Ye、Liang Ouyang

  DOI：10.1021/acs.jmedchem.1c01382

  日期：2021.12.23

  4 (BRD4) is an attractive epigenetic target in human cancers. Inhibiting the phosphorylation of BRD4 by casein kinase 2 (CK2) is a potential strategy to overcome drug resistance in cancer therapy. The present study describes the synthesis of multiple BRD4–CK2 dual inhibitors based on rational drug design, structure–activity relationship, and in vitro and in vivo evaluations, and 44e was identified to

  Bromodomain-containing protein 4 (BRD4) 是人类癌症中一个有吸引力的表观遗传靶点。通过酪蛋白激酶 2 (CK2) 抑制 BRD4 的磷酸化是克服癌症治疗耐药性的潜在策略。本研究描述了基于合理药物设计、结构-活性关系以及体外和体内评估的多种 BRD4-CK2 双重抑制剂的合成，并确定44e对 BRD4 具有有效且平衡的活性（IC 50 = 180 nM ) 和 CK2 (IC 50 = 230 nM)。体外实验表明，44e可以抑制MDA-MB-231和MDA-MB-468细胞的增殖并诱导细胞凋亡和自噬相关细胞死亡。在两种体内异种移植小鼠模型中，44e显示出有效的抗癌活性，且没有明显的毒性。综上所述，我们成功合成了第一个高效的 BRD4-CK2 双重抑制剂，有望成为三阴性乳腺癌 (TNBC) 的一种有吸引力的治疗策略。