2,2′-(naphthalene-1,4-diylbis(((4-acetamidophenyl)sulfonyl)-azanediyl))diacetic acid

• 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-acetamidophenyl)sulfonyl)-azanediyl))diacetic acid
• 英文别名: 2-[(4-Acetamidophenyl)sulfonyl-[4-[(4-acetamidophenyl)sulfonyl-(carboxymethyl)amino]naphthalen-1-yl]amino]acetic acid；2-[(4-acetamidophenyl)sulfonyl-[4-[(4-acetamidophenyl)sulfonyl-(carboxymethyl)amino]naphthalen-1-yl]amino]acetic acid
• 化学式: C₃₀H₂₈N₄O₁₀S₂
• 分子量: 668.705
• InChiKey: JJOFXZVJJGEQCK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  224
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  1-氨基-4-硝基萘 在 吡啶 、 palladium on activated charcoal 、 氢气 、 potassium carbonate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 11.0h， 生成 2,2′-(naphthalene-1,4-diylbis(((4-acetamidophenyl)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

文献信息

• 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.
• Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors
  作者：Meng-Chen Lu、Shi-Jie Tan、Jian-Ai Ji、Zhi-Yun Chen、Zhen-Wei Yuan、Qi-Dong You、Zheng-Yu Jiang

  DOI：10.1021/acsmedchemlett.5b00407

  日期：2016.9.8

  Directly disrupting the Keap1-Nrf2 protein protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC50 = 15.8 nM) in an in vitro fluorescence polarization assay. Physicochemical property determination demonstrated that ditetrazole replacement can improve the drug-like property, including elevation of pK(a), log D, and transcellular permeability. Additionally, 7 is more efficacious than 2 on inducing the expression of Nrf2-dependent gene products in cells. This study provides an alternative way to replace the diacetic moiety and occupy the polar subpockets in Keap1, which can benefit the subsequent development of Keap1-Nrf2 PPI inhibitor.