Exploring Biginelli-based scaffolds as A2B 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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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332224002294 |
| _version_ | 1797248405470183424 |
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| author | Rubén Prieto-Díaz Hugo Fojo-Carballo Maria Majellaro Tana Tandarić Jhonny Azuaje José Brea María I. Loza Jorge Barbazán Glòria Salort Meera Chotalia Iván Rodríguez-Pampín Ana Mallo-Abreu M. Rita Paleo Xerardo García-Mera Francisco Ciruela Hugo Gutiérrez-de-Terán Eddy Sotelo |
| author_facet | Rubén Prieto-Díaz Hugo Fojo-Carballo Maria Majellaro Tana Tandarić Jhonny Azuaje José Brea María I. Loza Jorge Barbazán Glòria Salort Meera Chotalia Iván Rodríguez-Pampín Ana Mallo-Abreu M. Rita Paleo Xerardo García-Mera Francisco Ciruela Hugo Gutiérrez-de-Terán Eddy Sotelo |
| author_sort | Rubén Prieto-Díaz |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-07T14:29:57Z |
| format | Article |
| id | doaj.art-49588aec46c84378975a623bef5f1ed4 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-24T20:14:04Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-49588aec46c84378975a623bef5f1ed42024-03-23T06:22:49ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-04-01173116345Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agentsRubén Prieto-Díaz0Hugo Fojo-Carballo1Maria Majellaro2Tana Tandarić3Jhonny Azuaje4José Brea5María I. Loza6Jorge Barbazán7Glòria Salort8Meera Chotalia9Iván Rodríguez-Pampín10Ana Mallo-Abreu11M. Rita Paleo12Xerardo García-Mera13Francisco Ciruela14Hugo Gutiérrez-de-Terán15Eddy Sotelo16Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainCentro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainCentro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Corresponding authors at: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain.Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Biomedical Centre, Uppsala 75124, SwedenCentro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainCentro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Corresponding author at: Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain.Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainGrupo de Oncología Médica Traslacional (ONCOMET), Instituto de Investigación Sanitaria, Santiago de Compostela (IDIS), Hospital Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela 15706, Spain; Corresponding authors.Unidad de Farmacología, Departamento de Patología y Terapéutica Experimental, Facultad de Medicina y Ciencias de la Salud, Instituto de Neurociencia, Universitat de Barcelona, L’Hospitalet de Llobregat 08907, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, L’Hospitalet de Llobregat 08907, Spain; Laboratorio de Neurofarmacología, Institut Universitari d′Investigació en Ciències de la Salut (IUNICS), Institut d′investigació Sanitària Illes Balears (IdISBa), University of the Balearic Islands, Palma de Mallorca 07122, SpainCentro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainCentro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainCentro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainCentro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, SpainUnidad de Farmacología, Departamento de Patología y Terapéutica Experimental, Facultad de Medicina y Ciencias de la Salud, Instituto de Neurociencia, Universitat de Barcelona, L’Hospitalet de Llobregat 08907, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, L’Hospitalet de Llobregat 08907, SpainScience for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Biomedical Centre, Uppsala 75124, Sweden; Corresponding authors.Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Corresponding authors at: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain.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.http://www.sciencedirect.com/science/article/pii/S0753332224002294A2B adenosine receptorColorectal cancerBiginelli reaction |
| spellingShingle | Rubén Prieto-Díaz Hugo Fojo-Carballo Maria Majellaro Tana Tandarić Jhonny Azuaje José Brea María I. Loza Jorge Barbazán Glòria Salort Meera Chotalia Iván Rodríguez-Pampín Ana Mallo-Abreu M. Rita Paleo Xerardo García-Mera Francisco Ciruela Hugo Gutiérrez-de-Terán Eddy Sotelo Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents Biomedicine & Pharmacotherapy A2B adenosine receptor Colorectal cancer Biginelli reaction |
| title | Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents |
| title_full | Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents |
| title_fullStr | Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents |
| title_full_unstemmed | Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents |
| title_short | Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents |
| title_sort | exploring biginelli based scaffolds as a2b adenosine receptor antagonists unveiling novel structure activity relationship trends lead compounds and potent colorectal anticancer agents |
| topic | A2B adenosine receptor Colorectal cancer Biginelli reaction |
| url | http://www.sciencedirect.com/science/article/pii/S0753332224002294 |
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