Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents

Antagonists of the A2B adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyc...

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Autores: Prieto-Díaz, Rubén, Fojo-Carballo, Hugo, Majellaro, Maria, Tandarić, Tana, Azuaje, Jhonny, Brea, José, Loza, María I, Barbazán, Jorge, Salort Flaquer, Gloria, Chotalia, Meera, Rodríguez-Pampín, Iván, Mallo-Abreu, Ana, Rita Paleo, M, García-Mera, Xerardo, Ciruela, Francisco, Gutiérrez-de-Terán, Hugo, Sotelo, Eddy
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Conselleria de Salut i Consum del Govern de les Illes Balears
Repositorio:Docusalut
Idioma:inglés
OAI Identifier:oai:docusalut.com:20.500.13003/24962
Acceso en línea:https://hdl.handle.net/20.500.13003/24962
Access Level:acceso abierto
Palabra clave:A(2B) adenosine receptor
Biginelli reaction
Colorectal cancer
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spelling Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agentsPrieto-Díaz, RubénFojo-Carballo, HugoMajellaro, MariaTandarić, TanaAzuaje, JhonnyBrea, JoséLoza, María IBarbazán, JorgeSalort Flaquer, GloriaChotalia, MeeraRodríguez-Pampín, IvánMallo-Abreu, AnaRita Paleo, MGarcía-Mera, XerardoCiruela, FranciscoGutiérrez-de-Terán, HugoSotelo, EddyA(2B) adenosine receptorBiginelli reactionColorectal cancerAntagonists of the A2B adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A2BAR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (Ki < 100 nM) and outstanding selectivity for A2BAR. From these, five molecules corresponding to the new benzothiazole scaffold were below the Ki < 10 nM threshold, in addition to a novel dual A2A/A2B antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A2BAR. Two A2BAR selective antagonists and the dual A2AAR/A2BAR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A2BAR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A2BAR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A2AAR antagonism in the context of immune checkpoint inhibition.Elsevier20242024-04-0120242024-04-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.13003/24962reponame:Docusalutinstname:Conselleria de Salut i Consum del Govern de les Illes BalearsInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docusalut.com:20.500.13003/249622026-06-22T12:44:07Z
dc.title.none.fl_str_mv Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
title Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
spellingShingle Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
Prieto-Díaz, Rubén
A(2B) adenosine receptor
Biginelli reaction
Colorectal cancer
title_short Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
title_full Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
title_fullStr Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
title_full_unstemmed Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
title_sort Exploring Biginelli-based scaffolds as A adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
dc.creator.none.fl_str_mv Prieto-Díaz, Rubén
Fojo-Carballo, Hugo
Majellaro, Maria
Tandarić, Tana
Azuaje, Jhonny
Brea, José
Loza, María I
Barbazán, Jorge
Salort Flaquer, Gloria
Chotalia, Meera
Rodríguez-Pampín, Iván
Mallo-Abreu, Ana
Rita Paleo, M
García-Mera, Xerardo
Ciruela, Francisco
Gutiérrez-de-Terán, Hugo
Sotelo, Eddy
author Prieto-Díaz, Rubén
author_facet Prieto-Díaz, Rubén
Fojo-Carballo, Hugo
Majellaro, Maria
Tandarić, Tana
Azuaje, Jhonny
Brea, José
Loza, María I
Barbazán, Jorge
Salort Flaquer, Gloria
Chotalia, Meera
Rodríguez-Pampín, Iván
Mallo-Abreu, Ana
Rita Paleo, M
García-Mera, Xerardo
Ciruela, Francisco
Gutiérrez-de-Terán, Hugo
Sotelo, Eddy
author_role author
author2 Fojo-Carballo, Hugo
Majellaro, Maria
Tandarić, Tana
Azuaje, Jhonny
Brea, José
Loza, María I
Barbazán, Jorge
Salort Flaquer, Gloria
Chotalia, Meera
Rodríguez-Pampín, Iván
Mallo-Abreu, Ana
Rita Paleo, M
García-Mera, Xerardo
Ciruela, Francisco
Gutiérrez-de-Terán, Hugo
Sotelo, Eddy
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv A(2B) adenosine receptor
Biginelli reaction
Colorectal cancer
topic A(2B) adenosine receptor
Biginelli reaction
Colorectal cancer
description Antagonists of the A2B adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A2BAR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (Ki < 100 nM) and outstanding selectivity for A2BAR. From these, five molecules corresponding to the new benzothiazole scaffold were below the Ki < 10 nM threshold, in addition to a novel dual A2A/A2B antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A2BAR. Two A2BAR selective antagonists and the dual A2AAR/A2BAR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A2BAR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A2BAR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A2AAR antagonism in the context of immune checkpoint inhibition.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-04-01
2024
2024-04-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.13003/24962
url https://hdl.handle.net/20.500.13003/24962
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Docusalut
instname:Conselleria de Salut i Consum del Govern de les Illes Balears
instname_str Conselleria de Salut i Consum del Govern de les Illes Balears
reponame_str Docusalut
collection Docusalut
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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