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dc.contributor.authorSchepetkin, Igor A.
dc.contributor.authorKarpenko, Oleksander S.
dc.contributor.authorKovrizhina, Anastasia R.
dc.contributor.authorKirpotina, Liliya N.
dc.contributor.authorKhlebnikov, Andrei I.
dc.contributor.authorChekal, Stepan I.
dc.contributor.authorRadudik, Alevtyna V.
dc.contributor.authorShybinska, Maryna O.
dc.contributor.authorQuinn, Mark T.
dc.date.accessioned2023-08-08T18:04:10Z
dc.date.available2023-08-08T18:04:10Z
dc.date.issued2023-06
dc.identifier.citationSchepetkin IA, Karpenko OS, Kovrizhina AR, Kirpotina LN, Khlebnikov AI, Chekal SI, Radudik AV, Shybinska MO, Quinn MT. Novel Tryptanthrin Derivatives with Selectivity as c–Jun N–Terminal Kinase (JNK) 3 Inhibitors. Molecules. 2023; 28(12):4806. https://doi.org/10.3390/molecules28124806en_US
dc.identifier.issn1420-3049
dc.identifier.urihttps://scholarworks.montana.edu/xmlui/handle/1/18053
dc.description.abstractThe c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including cell proliferation and differentiation, cell survival, and inflammation. Because of emerging data suggesting that JNK3 may play an important role in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease, as well as cancer pathogenesis, we sought to identify JNK inhibitors with increased selectivity for JNK3. A panel of 26 novel tryptanthrin-6-oxime analogs was synthesized and evaluated for JNK1-3 binding (Kd) and inhibition of cellular inflammatory responses. Compounds 4d (8-methoxyindolo[2,1-b]quinazolin-6,12-dione oxime) and 4e (8-phenylindolo[2,1-b]quinazolin-6,12-dione oxime) had high selectivity for JNK3 versus JNK1 and JNK2 and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue cells and interleukin-6 (IL-6) production by MonoMac-6 monocytic cells in the low micromolar range. Likewise, compounds 4d, 4e, and pan-JNK inhibitor 4h (9-methylindolo[2,1-b]quinazolin-6,12-dione oxime) decreased LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of these compounds in the JNK3 catalytic site that were in agreement with the experimental data on JNK3 binding. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems with selectivity for JNK3.en_US
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.rightscc-byen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectanti-inflammatoryen_US
dc.subjectc-Jun N-terminal kinaseen_US
dc.subjectmolecular dockingen_US
dc.subjectnuclear factor-κBen_US
dc.subjectoximeen_US
dc.subjectselective kinase inhibitoren_US
dc.subjecttryptanthrinen_US
dc.titleNovel Tryptanthrin Derivatives with Selectivity as c–Jun N–Terminal Kinase (JNK) 3 Inhibitorsen_US
dc.typeArticleen_US
mus.citation.extentfirstpage1en_US
mus.citation.extentlastpage24en_US
mus.citation.issue12en_US
mus.citation.journaltitleMoleculesen_US
mus.citation.volume28en_US
mus.identifier.doi10.3390/molecules28124806en_US
mus.relation.collegeCollege of Agricultureen_US
mus.relation.departmentMicrobiology & Immunology.en_US
mus.relation.universityMontana State University - Bozemanen_US
mus.data.thumbpage11en_US


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