diethyl 2,2'-(naphthalene-1,4-diyl)bis(((4-methoxyphenyl)sulfonyl)azanediyl)diacetate | 1567836-16-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: diethyl 2,2'-(naphthalene-1,4-diyl)bis(((4-methoxyphenyl)sulfonyl)azanediyl)diacetate
• 英文别名: Ethyl 2-[[4-[(2-ethoxy-2-oxoethyl)-(4-methoxyphenyl)sulfonylamino]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetate；ethyl 2-[[4-[(2-ethoxy-2-oxoethyl)-(4-methoxyphenyl)sulfonylamino]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetate
• CAS: 1567836-16-1
• 化学式: C₃₂H₃₄N₂O₁₀S₂
• 分子量: 670.761
• InChiKey: IKLBKEUFWRKWKQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  46
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  163
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  diethyl 2,2'-(naphthalene-1,4-diyl)bis(((4-methoxyphenyl)sulfonyl)azanediyl)diacetate 在 甲醇 、 4-二甲氨基吡啶 、 水 、 N,N'-二环己基碳二亚胺 、 sodium hydroxide 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 生成
  参考文献：
  名称：

  一种Keap1-Nrf2 PPI抑制剂前药、制备方法和用途

  摘要：

  本发明公开了一种Keap1‑Nrf2 PPI抑制剂前药、制备方法和用途。本发明提供的前药P‑168将活性化合物168的极性羧酸基团封闭，脂溶性得到提高，透膜性及成药性均有效改善；该前药P‑168在高ROS条件下被还原，释放出药效团168和荧光基团香豆素，激活Nrf2及其下游基因的表达，发挥抗炎活性，同时释放荧光实现可视化监测。

  公开号：

  CN112321620B
• 作为产物：
  描述：

  1-氨基-4-硝基萘 在 吡啶 、 palladium on activated charcoal 、 氢气 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 9.0h， 生成 diethyl 2,2'-(naphthalene-1,4-diyl)bis(((4-methoxyphenyl)sulfonyl)azanediyl)diacetate
  参考文献：
  名称：

  基于分子结合决定因素分析的有效Keap1-Nrf2蛋白-蛋白质相互作用抑制剂的发现

  摘要：

  已知Keap1介导Nrf2的泛素化，Nrf2是抗氧化反应的主要调节剂。直接中断Keap1-Nrf2相互作用已成为开发新型抗氧化剂，抗炎剂和抗癌剂的一种有前途的策略。上Keap1的的分子结合决定簇分析的基础上，我们成功地设计和表征Keap1的-Nrf2的，化合物的最有力的蛋白质-蛋白质相互作用（PPI）抑制剂2，与ķ d 3.59纳米的值绑定到Keap1的首次到一位数纳摩尔。化合物2可有效破坏Nrf2-Keap1与EC 50的相互作用在荧光偏振测定中为28.6nM。它也可以剂量依赖的方式在基于细胞的ARE-荧光素酶报告基因分析中激活Nrf2转录活性。Nrf2转录目标的qRT-PCR结果给出了一致的结果。这些结果证实，通过小分子可以完全，直接，高效地中断Keap1-Nrf2 PPI。

  DOI：

  10.1021/jm5000529

文献信息

• A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity
  作者：Kim T. Tran、Jakob S. Pallesen、Sara M. Ø. Solbak、Dilip Narayanan、Amina Baig、Jie Zang、Alejandro Aguayo-Orozco、Rosa M. C. Carmona、Anthony D. Garcia、Anders Bach

  DOI：10.1021/acs.jmedchem.9b00723

  日期：2019.9.12

  Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.
• Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators
  作者：Atul D. Jain、Haranatha Potteti、Benjamin G. Richardson、Laura Kingsley、Julia P. Luciano、Aya F. Ryuzoji、Hyun Lee、Aleksej Krunic、Andrew D. Mesecar、Sekhar P. Reddy、Terry W. Moore

  DOI：10.1016/j.ejmech.2015.08.049

  日期：2015.10

  Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a K-d of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Structure–Activity and Structure–Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1–Nrf2 Protein–Protein Interaction Inhibitor
  作者：Zheng-Yu Jiang、Li−Li Xu、Meng-Chen Lu、Zhi-Yun Chen、Zhen-Wei Yuan、Xiao-Li Xu、Xiao-Ke Guo、Xiao-Jin Zhang、Hao-Peng Sun、Qi-Dong You

  DOI：10.1021/acs.jmedchem.5b00185

  日期：2015.8.27

  Directly disrupting the Keap1-Nrf2 protein protein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1-Nrf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure activity and structure property relationships of the ring systems to improve the drug-like properties. Compound 18e, which bore p-acetamido substituents on the side chain phenyl rings, was the best choice for balancing PPI inhibition activity, physicochemical properties, and cellular Nrf2 activity. Cell-based experiments with 18e showed that the Keap1-Nrf2 PPI inhibitor can activate Nrf2 and induce the expression of Nrf2 downstream proteins in an Nrf2-dependent manner. An exploratory in vivo experiment was carried out to further evaluate the anti-inflammatory effects of 18e in a LPS-challenged mouse model. The primary results indicated that 18e could reduce the level of circulating pro-inflammatory cytokines induced by LPS and relieve the inflammatory response.
• Discovery of Potent Keap1–Nrf2 Protein–Protein Interaction Inhibitor Based on Molecular Binding Determinants Analysis
  作者：Zheng-Yu Jiang、Meng-Chen Lu、Li−Li Xu、Ting-Ting Yang、Mei-Yang Xi、Xiao-Li Xu、Xiao-Ke Guo、Xiao-Jin Zhang、Qi-Dong You、Hao-Peng Sun

  DOI：10.1021/jm5000529

  日期：2014.3.27

  interrupting the Keap1–Nrf2 interaction has been emerged as a promising strategy to develop novel class of antioxidant, antiinflammatory, and anticancer agents. On the basis of the molecular binding determinants analysis of Keap1, we successfully designed and characterized the most potent protein–protein interaction (PPI) inhibitor of Keap1–Nrf2, compound 2, with KD value of 3.59 nM binding to Keap1 for

  已知Keap1介导Nrf2的泛素化，Nrf2是抗氧化反应的主要调节剂。直接中断Keap1-Nrf2相互作用已成为开发新型抗氧化剂，抗炎剂和抗癌剂的一种有前途的策略。上Keap1的的分子结合决定簇分析的基础上，我们成功地设计和表征Keap1的-Nrf2的，化合物的最有力的蛋白质-蛋白质相互作用（PPI）抑制剂2，与ķ d 3.59纳米的值绑定到Keap1的首次到一位数纳摩尔。化合物2可有效破坏Nrf2-Keap1与EC 50的相互作用在荧光偏振测定中为28.6nM。它也可以剂量依赖的方式在基于细胞的ARE-荧光素酶报告基因分析中激活Nrf2转录活性。Nrf2转录目标的qRT-PCR结果给出了一致的结果。这些结果证实，通过小分子可以完全，直接，高效地中断Keap1-Nrf2 PPI。
• 一种Keap1-Nrf2 PPI抑制剂前药、制备方法和用途
  申请人：中国药科大学

  公开号：CN112321620B

  公开（公告）日：2022-03-29

  本发明公开了一种Keap1‑Nrf2 PPI抑制剂前药、制备方法和用途。本发明提供的前药P‑168将活性化合物168的极性羧酸基团封闭，脂溶性得到提高，透膜性及成药性均有效改善；该前药P‑168在高ROS条件下被还原，释放出药效团168和荧光基团香豆素，激活Nrf2及其下游基因的表达，发挥抗炎活性，同时释放荧光实现可视化监测。