N-(tert-butyl)-4-chloroquinolin-2-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-(tert-butyl)-4-chloroquinolin-2-amine
• 英文别名: N-tert-butyl-4-chloroquinolin-2-amine
• 化学式: C₁₃H₁₅ClN₂
• 分子量: 234.728
• InChiKey: HNINYQIVSCXCFN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  24.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-(tert-butyl)-4-chloroquinolin-2-amine 在 三氟乙酸 作用下， 以 异丙醇 为溶剂， 反应 3.0h， 生成 4-(piperazin-1-yl)quinolin-2-amine
  参考文献：
  名称：

  Developing Inhibitors of the p47phox–p22phox Protein–Protein Interaction by Fragment-Based Drug Discovery

  摘要：

  Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species and contributes to oxidative stress. The p47phox-p22phox interaction is critical for the activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2500 fragments using fluorescence polarization and a thermal shift assay and validation by surface plasmon resonance, we found eight hits toward the tandem SH3 domain of p47phox (p47phox(SH3A-B)) with K-D values of 400-600 mu M. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phox(SH3A-B) and these competed with p22phox for binding to p47phox(SH3A-B). Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phox(SH3A-B)-p22phox interaction (K-i of 20 mu M). Thereby, we reveal a new way of targeting p47phox and present the first report of drug-like molecules with the ability to bind p47phox and inhibit its interaction with p22phox.

  DOI：

  10.1021/acs.jmedchem.9b01492
• 作为产物：
  描述：

  4-氯喹啉 在 4-甲苯磺酸酐 、 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 N-(tert-butyl)-4-chloroquinolin-2-amine
  参考文献：
  名称：

  [EN] SMALL-MOLECULE NADPH OXIDASE 2 INHIBITORS
  [FR] INHIBITEURS DE NADPH OXYDASE 2 À PETITE MOLÉCULE

  摘要：

  该发明提供了公式（II）的化合物，其中包括两个末端的2-氨基喹啉基团。它们是新颖且有效的 p47phox-p22phox 蛋白质相互作用抑制剂，可以抑制多亚基和产生超氧化物的 NADPH 氧化酶 2 复合物的组装和激活。这些化合物在治疗上具有重要意义，因为它们可以减少 NADPH 氧化酶 2 在产生活性氧物种（ROS）和氧化应激中起主要作用的疾病中的细胞损伤。

  公开号：

  WO2021105497A1

文献信息

• [EN] SMALL-MOLECULE NADPH OXIDASE 2 INHIBITORS<br/>[FR] INHIBITEURS DE NADPH OXYDASE 2 À PETITE MOLÉCULE
  申请人：UNIV COPENHAGEN

  公开号：WO2021105497A1

  公开（公告）日：2021-06-03

  The invention provides compounds of Formula (II) which comprise two terminal 2-aminoquinoline moieties. They are novel and potent inhibitors of the p47phox-p22phox protein-protein interaction that can inhibit the assembly and thus activation of the multisubunit and superoxide-generating NADPH oxidase 2 complex. The compounds are therapeutically relevant as they can reduce cell damage in diseases where NADPH oxidase 2 is a major contributor to generation of reactive oxygen species (ROS) and oxidative stress.

  该发明提供了公式（II）的化合物，其中包括两个末端的2-氨基喹啉基团。它们是新颖且有效的 p47phox-p22phox 蛋白质相互作用抑制剂，可以抑制多亚基和产生超氧化物的 NADPH 氧化酶 2 复合物的组装和激活。这些化合物在治疗上具有重要意义，因为它们可以减少 NADPH 氧化酶 2 在产生活性氧物种（ROS）和氧化应激中起主要作用的疾病中的细胞损伤。
• Developing Inhibitors of the p47phox–p22phox Protein–Protein Interaction by Fragment-Based Drug Discovery
  作者：Sara Marie Øie Solbak、Jie Zang、Dilip Narayanan、Lars Jakobsen Høj、Saskia Bucciarelli、Charlotte Softley、Sebastian Meier、Annette Eva Langkilde、Charlotte Held Gotfredsen、Michael Sattler、Anders Bach

  DOI：10.1021/acs.jmedchem.9b01492

  日期：2020.2.13

  Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species and contributes to oxidative stress. The p47phox-p22phox interaction is critical for the activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2500 fragments using fluorescence polarization and a thermal shift assay and validation by surface plasmon resonance, we found eight hits toward the tandem SH3 domain of p47phox (p47phox(SH3A-B)) with K-D values of 400-600 mu M. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phox(SH3A-B) and these competed with p22phox for binding to p47phox(SH3A-B). Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phox(SH3A-B)-p22phox interaction (K-i of 20 mu M). Thereby, we reveal a new way of targeting p47phox and present the first report of drug-like molecules with the ability to bind p47phox and inhibit its interaction with p22phox.