Synthesis and anti-inflammatory evaluation of a library of chiral derivatives of xanthones conjugated with proteinogenic amino acids

Detalhes bibliográficos
Autor(a) principal: Vieira, Sara Filipa Fontoura
Data de Publicação: 2023
Outros Autores: Araújo, Joana, Gonçalves, Virgínia M. F., Fernandes, Carla, Pinto, Madalena, Ferreira, Helena Susana Costa Machado, Neves, N. M., Tiritan, Maria Elizabeth
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.
id RCAP_54940d3e03523ce8f648982680bbcdae
oai_identifier_str oai:repositorium.sdum.uminho.pt:1822/85730
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling 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
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 mluisa.alvim@gmail.com
_version_ 1817544758601449472