2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways
Autor(a) principal: | |
---|---|
Data de Publicação: | 2017 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10198/14519 |
Resumo: | In response to an inflammatory stimulus, arachidonic acid (AA), the main polyunsaturated fatty acid present in the phospholipid layer of cell membranes, is released and metabolized to a series of eicosanoids. These bioactive lipid mediators of inflammation arise physiologically through the action of the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenases (constitutive COX-1 and inducible COX-2). It is believed that dual inhibition of 5-LOX and COXs may have a higher beneficial impact in the treatment of inflammatory disorders rather than the inhibition of each enzyme. With this demand for new dual-acting anti-inflammatory agents, a range of 2,3-diarylxanthones were tested through their ability to interact in the AA metabolism. In vitro anti-inflammatory activity was evaluated through the inhibition of 5-LOX-catalyzed leukotriene B4 (LTB4) formation in human neutrophils and inhibition of COX-1- and COX-2-catalyzed prostaglandin E2 (PGE2) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB4 production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC50 ∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE2 production presented IC50 values from 1 to 7 μM, exhibiting a structural feature with at least one non-substituted aryl group. All the studied arylxanthones were ineffective to prevent the formation of PGE2 catalyzed by COX-2, up to the maximum concentration of 100 μM. The ability of the tested 2,3-diarylxanthones to interact with both 5-LOX and COX-1 pathways constitutes an important step in the research of novel dual-acting anti-inflammatory drugs. |
id |
RCAP_5945d2aaaab36292d8edfd9ccbf8df15 |
---|---|
oai_identifier_str |
oai:bibliotecadigital.ipb.pt:10198/14519 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathwaysXanthones5-LOXCOX-1COX-2Human neutrophilsHuman whole-blood assaysIn response to an inflammatory stimulus, arachidonic acid (AA), the main polyunsaturated fatty acid present in the phospholipid layer of cell membranes, is released and metabolized to a series of eicosanoids. These bioactive lipid mediators of inflammation arise physiologically through the action of the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenases (constitutive COX-1 and inducible COX-2). It is believed that dual inhibition of 5-LOX and COXs may have a higher beneficial impact in the treatment of inflammatory disorders rather than the inhibition of each enzyme. With this demand for new dual-acting anti-inflammatory agents, a range of 2,3-diarylxanthones were tested through their ability to interact in the AA metabolism. In vitro anti-inflammatory activity was evaluated through the inhibition of 5-LOX-catalyzed leukotriene B4 (LTB4) formation in human neutrophils and inhibition of COX-1- and COX-2-catalyzed prostaglandin E2 (PGE2) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB4 production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC50 ∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE2 production presented IC50 values from 1 to 7 μM, exhibiting a structural feature with at least one non-substituted aryl group. All the studied arylxanthones were ineffective to prevent the formation of PGE2 catalyzed by COX-2, up to the maximum concentration of 100 μM. The ability of the tested 2,3-diarylxanthones to interact with both 5-LOX and COX-1 pathways constitutes an important step in the research of novel dual-acting anti-inflammatory drugs.Sincere thanks are expressed to Faculdade de Farmácia da Universidade do Porto, Universidade de Aveiro, Instituto Politécnico de Bragança, Fundação para a Ciência e a Tecnologia (FCT, Portugal), Ministério da Educação e Ciência, European Union, FEDER, PT 2020, QREN, and COMPETE funding UCIBIO, REQUIMTE [(PT2020 UID/MULTI/04378/2013 - POCI/01/0145/FEDER/007728), (NORTE-01-0145-FEDER-000024), and (PTDC/QEQ-QAN/1742/2014 – POCI-01-0145- FEDER-016530)] and QOPNA (FCT UID/QUI/00062/2013) Research Units and also to the Portuguese National NMR Network (RNRMN). We gratefully acknowledge Graça Porto and the nursing staff of the Centro Hospitalar do Porto - Hospital de Santo António blood bank for the collaboration in the recruitment of blood donors involved in the present work.Springer VerlagBiblioteca Digital do IPBSantos, Clementina M.M.Ribeiro, DanielaSilva, ArturFernandes, Eduarda2017-09-22T10:59:41Z20172017-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10198/14519engSantos, Clementina M.M.; Ribeiro, Daniela; Silva, Artur; Fernandes, Eduarda (2017). 2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways. Inflammation. ISSN 0360-3997. 40:3, p. 956-96410.1007/s10753-017-0540-6info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-21T10:34:03Zoai:bibliotecadigital.ipb.pt:10198/14519Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T23:04:20.220931Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways |
title |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways |
spellingShingle |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways Santos, Clementina M.M. Xanthones 5-LOX COX-1 COX-2 Human neutrophils Human whole-blood assays |
title_short |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways |
title_full |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways |
title_fullStr |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways |
title_full_unstemmed |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways |
title_sort |
2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways |
author |
Santos, Clementina M.M. |
author_facet |
Santos, Clementina M.M. Ribeiro, Daniela Silva, Artur Fernandes, Eduarda |
author_role |
author |
author2 |
Ribeiro, Daniela Silva, Artur Fernandes, Eduarda |
author2_role |
author author author |
dc.contributor.none.fl_str_mv |
Biblioteca Digital do IPB |
dc.contributor.author.fl_str_mv |
Santos, Clementina M.M. Ribeiro, Daniela Silva, Artur Fernandes, Eduarda |
dc.subject.por.fl_str_mv |
Xanthones 5-LOX COX-1 COX-2 Human neutrophils Human whole-blood assays |
topic |
Xanthones 5-LOX COX-1 COX-2 Human neutrophils Human whole-blood assays |
description |
In response to an inflammatory stimulus, arachidonic acid (AA), the main polyunsaturated fatty acid present in the phospholipid layer of cell membranes, is released and metabolized to a series of eicosanoids. These bioactive lipid mediators of inflammation arise physiologically through the action of the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenases (constitutive COX-1 and inducible COX-2). It is believed that dual inhibition of 5-LOX and COXs may have a higher beneficial impact in the treatment of inflammatory disorders rather than the inhibition of each enzyme. With this demand for new dual-acting anti-inflammatory agents, a range of 2,3-diarylxanthones were tested through their ability to interact in the AA metabolism. In vitro anti-inflammatory activity was evaluated through the inhibition of 5-LOX-catalyzed leukotriene B4 (LTB4) formation in human neutrophils and inhibition of COX-1- and COX-2-catalyzed prostaglandin E2 (PGE2) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB4 production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC50 ∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE2 production presented IC50 values from 1 to 7 μM, exhibiting a structural feature with at least one non-substituted aryl group. All the studied arylxanthones were ineffective to prevent the formation of PGE2 catalyzed by COX-2, up to the maximum concentration of 100 μM. The ability of the tested 2,3-diarylxanthones to interact with both 5-LOX and COX-1 pathways constitutes an important step in the research of novel dual-acting anti-inflammatory drugs. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-09-22T10:59:41Z 2017 2017-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10198/14519 |
url |
http://hdl.handle.net/10198/14519 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Santos, Clementina M.M.; Ribeiro, Daniela; Silva, Artur; Fernandes, Eduarda (2017). 2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathways. Inflammation. ISSN 0360-3997. 40:3, p. 956-964 10.1007/s10753-017-0540-6 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Springer Verlag |
publisher.none.fl_str_mv |
Springer Verlag |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799135290598621184 |