N,N'-(naphthalene-1,4-diyl)bis(3-methoxybenzenesulfonamide)

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N,N'-(naphthalene-1,4-diyl)bis(3-methoxybenzenesulfonamide)
• 英文别名: 3-methoxy-N-[4-[(3-methoxyphenyl)sulfonylamino]naphthalen-1-yl]benzenesulfonamide
• 化学式: C₂₄H₂₂N₂O₆S₂
• 分子量: 498.58
• InChiKey: GRIQSZFMJIFQQJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N,N'-(naphthalene-1,4-diyl)bis(3-methoxybenzenesulfonamide) 在 palladium on activated charcoal 、 氢气 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 2,2′-(naphthalene-1,4-diylbis(((3-methoxyphenyl)sulfonyl)-azanediyl))diacetic acid
  参考文献：
  名称：

  Structure–Activity and Structure–Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1–Nrf2 Protein–Protein Interaction Inhibitor

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.5b00185
• 作为产物：
  描述：

  1-氨基-4-硝基萘 在 吡啶 、 palladium on activated charcoal 、 氢气 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 6.0h， 生成 N,N'-(naphthalene-1,4-diyl)bis(3-methoxybenzenesulfonamide)
  参考文献：
  名称：

  Structure–Activity and Structure–Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1–Nrf2 Protein–Protein Interaction Inhibitor

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.5b00185

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.
• 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.