Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors
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 interve...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.958687/full |
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| author | Igor A. Schepetkin Anastasia R. Kovrizhina Ksenia S. Stankevich Andrei I. Khlebnikov Liliya N. Kirpotina Mark T. Quinn Matthew J. Cook |
| author_facet | Igor A. Schepetkin Anastasia R. Kovrizhina Ksenia S. Stankevich Andrei I. Khlebnikov Liliya N. Kirpotina Mark T. Quinn Matthew J. Cook |
| author_sort | Igor A. Schepetkin |
| collection | DOAJ |
| description | 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 (Kd) 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 (Kd = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/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 μM, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, 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. |
| first_indexed | 2024-12-10T14:52:22Z |
| format | Article |
| id | doaj.art-4dda9abd3b5a4a1480568deef666b6e7 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-10T14:52:22Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-4dda9abd3b5a4a1480568deef666b6e72022-12-22T01:44:24ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.958687958687Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitorsIgor A. Schepetkin0Anastasia R. Kovrizhina1Ksenia S. Stankevich2Andrei I. Khlebnikov3Liliya N. Kirpotina4Mark T. Quinn5Matthew J. Cook6Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United StatesKizhner Research Center, Tomsk Polytechnic University, Tomsk, RussiaDepartment of Chemistry and Biochemistry, Montana State University, Bozeman, MT, United StatesKizhner Research Center, Tomsk Polytechnic University, Tomsk, RussiaDepartment of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United StatesDepartment of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United StatesDepartment of Chemistry and Biochemistry, Montana State University, Bozeman, MT, United StatesThe 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 (Kd) 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 (Kd = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/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 μM, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, 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.https://www.frontiersin.org/articles/10.3389/fphar.2022.958687/fullanti-inflammatory11H-indeno[1,2-b]quinoxalin-11-oneinterleukin-6c-Jun N-terminal kinasenuclear factor-κBoxime |
| spellingShingle | Igor A. Schepetkin Anastasia R. Kovrizhina Ksenia S. Stankevich Andrei I. Khlebnikov Liliya N. Kirpotina Mark T. Quinn Matthew J. Cook Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors Frontiers in Pharmacology anti-inflammatory 11H-indeno[1,2-b]quinoxalin-11-one interleukin-6 c-Jun N-terminal kinase nuclear factor-κB oxime |
| title | Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors |
| title_full | Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors |
| title_fullStr | Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors |
| title_full_unstemmed | Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors |
| title_short | Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors |
| title_sort | design synthesis and biological evaluation of novel o substituted tryptanthrin oxime derivatives as c jun n terminal kinase inhibitors |
| topic | anti-inflammatory 11H-indeno[1,2-b]quinoxalin-11-one interleukin-6 c-Jun N-terminal kinase nuclear factor-κB oxime |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.958687/full |
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