2,2'-(naphthalene-1,4-diylbis(((4-methoxyphenyl)sulfonyl)azanediyl))diacetamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2,2'-(naphthalene-1,4-diylbis(((4-methoxyphenyl)sulfonyl)azanediyl))diacetamide
• 英文别名: 2,2′-(naphthalene-1,4-diylbis(((4-methoxyphenyl)sulfonyl)azanediyl))diacetamide；2,2'-(Naphthalene-1,4-Diylbis(((4-Methoxyphenyl)sulfonyl)azanediyl))diacetamide；2-[[4-[(2-amino-2-oxoethyl)-(4-methoxyphenyl)sulfonylamino]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetamide
• 化学式: C₂₈H₂₈N₄O₈S₂
• 分子量: 612.684
• InChiKey: ZUIXHSIMKQZYPV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  196
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  1-氨基-4-硝基萘 在 吡啶 、 5%-palladium/activated carbon 、 氢气 、 potassium carbonate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 20.0~100.0 ℃ 、101.33 kPa 条件下， 反应 122.0h， 生成 2,2'-(naphthalene-1,4-diylbis(((4-methoxyphenyl)sulfonyl)azanediyl))diacetamide
  参考文献：
  名称：

  A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.9b00723

文献信息

• 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.
• 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.