Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/85730 |
Resumo: | In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2–31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32–61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered. |
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Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acidsAnti-inflammatory activityChiralityChiral poolEnantioselectivityXanthonesIn recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2–31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32–61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered.This research was funded by national funds through the Foundation for Science and Technology (FCT) within the scope of UIDB/04423/2020 and UIDP/04423/2020 (Group of Marine Natural Products and Medicinal Chemistry—CIIMAR) and ERDF, as a result of the projects PTDC/CTAAMB/6686/2020, and PTDC/CTAAMB/0853/2021. It was also supported by the projects PATH (PD/00169/2013), HEALTH-UNORTE (NORTE-01-0145-FEDER-000039), and the NORTE 2020 Structured Project and co-funded by Norte2020 (NORTE-01-0145-FEDER-000021). S.F.V. acknowledges FCT for the Ph.D. grants of PD/BD/135246/2017 and COVID/BD/152012/2021.To all undergraduate students enrolled in this work and the projects: CHIRALBIOACTIVE-PI-3RL-IINFACTS-2019; XANTAAL-GI2-CESPU-2022; and Flav4Tumor-GI2-CESPU-2022.Multidisciplinary Digital Publishing InstituteUniversidade do MinhoVieira, Sara Filipa FontouraAraújo, JoanaGonçalves, Virgínia M. F.Fernandes, CarlaPinto, MadalenaFerreira, Helena Susana Costa MachadoNeves, N. M.Tiritan, Maria Elizabeth2023-06-192023-06-19T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/85730engVieira, S.F.; Araújo, J.; Gonçalves, V.M.F.; Fernandes, C.; Pinto, M.; Ferreira, H.; Neves, N.M.; Tiritan, M.E. Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids. Int. J. Mol. Sci. 2023, 24, 10357. https://doi.org/10.3390/ijms2412103571661-65961422-006710.3390/ijms24121035737373503https://www.mdpi.com/1422-0067/24/12/10357info: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:RCAAP2024-05-11T05:50:22Zoai:repositorium.sdum.uminho.pt:1822/85730Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-05-11T05:50:22Repositório 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 |
Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids |
title |
Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids |
spellingShingle |
Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids Vieira, Sara Filipa Fontoura Anti-inflammatory activity Chirality Chiral pool Enantioselectivity Xanthones |
title_short |
Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids |
title_full |
Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids |
title_fullStr |
Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids |
title_full_unstemmed |
Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids |
title_sort |
Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids |
author |
Vieira, Sara Filipa Fontoura |
author_facet |
Vieira, Sara Filipa Fontoura Araújo, Joana Gonçalves, Virgínia M. F. Fernandes, Carla Pinto, Madalena Ferreira, Helena Susana Costa Machado Neves, N. M. Tiritan, Maria Elizabeth |
author_role |
author |
author2 |
Araújo, Joana Gonçalves, Virgínia M. F. Fernandes, Carla Pinto, Madalena Ferreira, Helena Susana Costa Machado Neves, N. M. Tiritan, Maria Elizabeth |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Vieira, Sara Filipa Fontoura Araújo, Joana Gonçalves, Virgínia M. F. Fernandes, Carla Pinto, Madalena Ferreira, Helena Susana Costa Machado Neves, N. M. Tiritan, Maria Elizabeth |
dc.subject.por.fl_str_mv |
Anti-inflammatory activity Chirality Chiral pool Enantioselectivity Xanthones |
topic |
Anti-inflammatory activity Chirality Chiral pool Enantioselectivity Xanthones |
description |
In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2–31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32–61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-06-19 2023-06-19T00:00:00Z |
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 |
https://hdl.handle.net/1822/85730 |
url |
https://hdl.handle.net/1822/85730 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Vieira, S.F.; Araújo, J.; Gonçalves, V.M.F.; Fernandes, C.; Pinto, M.; Ferreira, H.; Neves, N.M.; Tiritan, M.E. Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids. Int. J. Mol. Sci. 2023, 24, 10357. https://doi.org/10.3390/ijms241210357 1661-6596 1422-0067 10.3390/ijms241210357 37373503 https://www.mdpi.com/1422-0067/24/12/10357 |
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 |
Multidisciplinary Digital Publishing Institute |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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mluisa.alvim@gmail.com |
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