期刊
FRONTIERS IN PHARMACOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.958687
关键词
anti-inflammatory; 11H-indeno[1; 2-b]quinoxalin-11-one; interleukin-6; c-Jun N-terminal kinase; nuclear factor-kappa B; oxime; tryptanthrin
资金
- National Institutes of Health IDeA Program Grants
- USDA National Institute of Food and Agriculture Hatch project [GM115371, GM103474]
- Montana State University Agricultural Experiment Station [1009546]
- Tomsk Polytechnic University development program Priority 2030
- [2030-NIP/IZ-009-0000-2022]
This study synthesized a panel of novel tryptanthrin oxime analogs and evaluated their binding affinity to JNK1-3 and inhibition of cellular inflammatory responses. Compound 1j exhibited high binding affinity to JNK1-3 and demonstrated anti-inflammatory activity by inhibiting the production of multiple proinflammatory cytokines. Molecular modeling confirmed the binding mode of 1j to JNK3.
The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNK represents an attractive target for therapeutic intervention. Herein, a panel of novel tryptanthrin oxime analogs were synthesized and evaluated for JNK1-3 binding (K-d) and inhibition of cellular inflammatory responses (IC50). Several compounds exhibited submicromolar JNK binding affinity, with the most potent inhibitor being 6-(acetoxyimino)indolo[2,1-b]quinazolin-12(6H)-one (1j), which demonstrated high JNK1-3 binding affinity (K-d = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-kappa B/activating protein 1 (NF-kappa B/AP-1) transcription activity in THP-1Blue cells and interleukin-6 (IL-6) production in MonoMac-6 monocytic cells (IC50 = 0.8 and 1.7 mu M, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1 alpha, IL-1 beta, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Likewise, 1j inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of selected compounds in the JNK3 catalytic site that were in agreement with the experimental JNK3 binding data. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据