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Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents
Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lip...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882468/ https://www.ncbi.nlm.nih.gov/pubmed/31752552 http://dx.doi.org/10.1080/14756366.2019.1693703 |
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author | Liu, Wandong Hou, Caiyun Li, Jiaming Ma, Xiaodong Zhang, Yanchun Hu, Mengqi Huang, Yuanzheng |
author_facet | Liu, Wandong Hou, Caiyun Li, Jiaming Ma, Xiaodong Zhang, Yanchun Hu, Mengqi Huang, Yuanzheng |
author_sort | Liu, Wandong |
collection | PubMed |
description | Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC(50)=1.95 µM) and COX-2 (IC(50)=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug. |
format | Online Article Text |
id | pubmed-6882468 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-68824682019-12-13 Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents Liu, Wandong Hou, Caiyun Li, Jiaming Ma, Xiaodong Zhang, Yanchun Hu, Mengqi Huang, Yuanzheng J Enzyme Inhib Med Chem Research Paper Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC(50)=1.95 µM) and COX-2 (IC(50)=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug. Taylor & Francis 2019-11-22 /pmc/articles/PMC6882468/ /pubmed/31752552 http://dx.doi.org/10.1080/14756366.2019.1693703 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Paper Liu, Wandong Hou, Caiyun Li, Jiaming Ma, Xiaodong Zhang, Yanchun Hu, Mengqi Huang, Yuanzheng Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents |
title | Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents |
title_full | Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents |
title_fullStr | Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents |
title_full_unstemmed | Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents |
title_short | Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents |
title_sort | discovery of talmapimod analogues as polypharmacological anti-inflammatory agents |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882468/ https://www.ncbi.nlm.nih.gov/pubmed/31752552 http://dx.doi.org/10.1080/14756366.2019.1693703 |
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