Development of Keap1-Nrf2 Protein-Protein Interaction Inhibitor Activating Intracellular Nrf2 Based on the Naphthalene-2-acetamide Scaffold, and its Anti-Inflammatory Effects.

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-09-03 DOI:10.1002/cmdc.202500474

Daisuke Yasuda, Kai Toyoshima, Koujin Kojima, Hanako Ishida, Kazuma Kaitoh, Riyo Imamura, Kayoko Kanamitsu, Hirotatsu Kojima, Megumi Funakoshi-Tago, Masanori Osawa, Tomoyuki Ohe, Tomoya Hirano

{"title":"Development of Keap1-Nrf2 Protein-Protein Interaction Inhibitor Activating Intracellular Nrf2 Based on the Naphthalene-2-acetamide Scaffold, and its Anti-Inflammatory Effects.","authors":"Daisuke Yasuda, Kai Toyoshima, Koujin Kojima, Hanako Ishida, Kazuma Kaitoh, Riyo Imamura, Kayoko Kanamitsu, Hirotatsu Kojima, Megumi Funakoshi-Tago, Masanori Osawa, Tomoyuki Ohe, Tomoya Hirano","doi":"10.1002/cmdc.202500474","DOIUrl":null,"url":null,"abstract":"<p><p>Nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) axis is an attractive therapeutic target for various intractable diseases. Although protein-protein interaction inhibitors against Keap1-Nrf2 have been developed over the past decade, more structural expansion is needed to improve efficacy. In this article, several candidate compounds are designed and synthesized as novel Nrf2 activators and their intracellular Nrf2-activating effects are evaluated. Among the synthesized compounds, a novel naphthalene-1,4-(4-ethoxybenzensulfonamide) bearing a tertiary acetamide side chain at the 2-position strongly activated intracellular Nrf2. Particularly, the pyrrolidine-type acetamide compound showed the strongest intracellular Nrf2 activation. X-ray cocrystallography revealed that this compound can bind to the DC domain of Keap1. Additionally, the pyrrolidine-type acetamide compound induced the mRNA expression of the representative Nrf2 target genes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Moreover, the compound exhibited anti-inflammatory effects in a lipopolysaccharide-stimulated macrophage cell line. Conclusively, these results suggest that the pyrrolidine-type naphthalene-2-acetamide is a promising compound for the development of Nrf2 activators that can be applied to treat inflammatory diseases.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500474"},"PeriodicalIF":3.4000,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202500474","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) axis is an attractive therapeutic target for various intractable diseases. Although protein-protein interaction inhibitors against Keap1-Nrf2 have been developed over the past decade, more structural expansion is needed to improve efficacy. In this article, several candidate compounds are designed and synthesized as novel Nrf2 activators and their intracellular Nrf2-activating effects are evaluated. Among the synthesized compounds, a novel naphthalene-1,4-(4-ethoxybenzensulfonamide) bearing a tertiary acetamide side chain at the 2-position strongly activated intracellular Nrf2. Particularly, the pyrrolidine-type acetamide compound showed the strongest intracellular Nrf2 activation. X-ray cocrystallography revealed that this compound can bind to the DC domain of Keap1. Additionally, the pyrrolidine-type acetamide compound induced the mRNA expression of the representative Nrf2 target genes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Moreover, the compound exhibited anti-inflammatory effects in a lipopolysaccharide-stimulated macrophage cell line. Conclusively, these results suggest that the pyrrolidine-type naphthalene-2-acetamide is a promising compound for the development of Nrf2 activators that can be applied to treat inflammatory diseases.

查看原文本刊更多论文

基于萘-2-乙酰胺支架活化细胞内Nrf2的Keap1-Nrf2蛋白-蛋白相互作用抑制剂的研制及其抗炎作用

核因子红系2相关因子2 （Nrf2）和kelch样ech相关蛋白1 （Keap1）轴是治疗各种顽固性疾病的一个有吸引力的靶点。尽管在过去的十年中已经开发了针对Keap1-Nrf2的蛋白-蛋白相互作用抑制剂，但需要更多的结构扩展来提高疗效。本文设计并合成了几种新型Nrf2激活剂候选化合物，并对其细胞内Nrf2激活作用进行了评价。在所合成的化合物中，一种新型萘-1,4-（4-乙氧基苯磺酰胺）在2位具有叔乙酰胺侧链，能强烈激活细胞内Nrf2。其中，吡咯烷类乙酰胺化合物的细胞内Nrf2活性最强。x射线共晶分析表明，该化合物可以与Keap1的DC结构域结合。此外，吡咯烷类乙酰胺化合物诱导Nrf2代表性靶基因血红素氧化酶-1和NAD(P)H：醌氧化还原酶1的mRNA表达。此外，该化合物在脂多糖刺激的巨噬细胞系中表现出抗炎作用。总之，这些结果表明，吡咯烷型萘-2-乙酰胺是一种有前景的化合物，可以开发用于治疗炎症性疾病的Nrf2激活剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.