3,4-Dihydropyrimidin-2(1H)-ones as Antagonists of the Human A2B Adenosine Receptor: Optimization, Structure–Activity Relationship Studies, and Enantiospecific Recognition
- María MajellaroMaría MajellaroCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by María Majellaro
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- Willem JespersWillem JespersDepartment of Cell and Molecular Biology, Uppsala University, SE-75124 Uppsala, SwedenMore by Willem Jespers
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- Abel CrespoAbel CrespoCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Abel Crespo
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- María J. NúñezMaría J. NúñezSNL, Departamento de Farmacología, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by María J. Núñez
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- Silvia NovioSilvia NovioSNL, Departamento de Farmacología, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Silvia Novio
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- Jhonny AzuajeJhonny AzuajeCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Jhonny Azuaje
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- Rubén Prieto-DíazRubén Prieto-DíazCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Rubén Prieto-Díaz
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- Claudia GioéClaudia GioéCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Claudia Gioé
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- Belma AlispahicBelma AlispahicDepartment of Cell and Molecular Biology, Uppsala University, SE-75124 Uppsala, SwedenMore by Belma Alispahic
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- José Brea*José Brea*Email: [email protected]. Phone: +34 881815459. Fax: +34-8818115474.Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by José Brea
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- María I. LozaMaría I. LozaCentro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by María I. Loza
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- Manuel Freire-GarabalManuel Freire-GarabalSNL, Departamento de Farmacología, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Manuel Freire-Garabal
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- Carlota Garcia-SantiagoCarlota Garcia-SantiagoSNL, Departamento de Farmacología, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Carlota Garcia-Santiago
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- Carlos Rodríguez-GarcíaCarlos Rodríguez-GarcíaCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Carlos Rodríguez-García
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- Xerardo García-MeraXerardo García-MeraDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Xerardo García-Mera
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- Olga CaamañoOlga CaamañoDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Olga Caamaño
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- Christian Fernandez-MasaguerChristian Fernandez-MasaguerDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Christian Fernandez-Masaguer
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- Javier F. SardinaJavier F. SardinaCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Javier F. Sardina
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- Angela StefanachiAngela StefanachiDipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, via Orabona 4, 70125 Bari, ItalyMore by Angela Stefanachi
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- Abdelaziz El MaatouguiAbdelaziz El MaatouguiCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Abdelaziz El Maatougui
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- Ana Mallo-AbreuAna Mallo-AbreuCentro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Ana Mallo-Abreu
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- Johan ÅqvistJohan ÅqvistDepartment of Cell and Molecular Biology, Uppsala University, SE-75124 Uppsala, SwedenMore by Johan Åqvist
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- Hugo Gutiérrez-de-Terán*Hugo Gutiérrez-de-Terán*Email: [email protected]. Phone: +46 18 471 5056. Fax: +46 18 536971.Department of Cell and Molecular Biology, Uppsala University, SE-75124 Uppsala, SwedenMore by Hugo Gutiérrez-de-Terán
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- Eddy Sotelo*Eddy Sotelo*Email: [email protected]. Phone: +34 881815732, +34 881814942. Fax: +34-881815704.Centro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, SpainMore by Eddy Sotelo
Abstract
We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate experiments. The series was analyzed with one of the most exhaustive free energy perturbation studies on a GPCR, obtaining an accurate model of the structure–activity relationship of this chemotype. The stereospecific binding modeled for this scaffold was confirmed by resolving the two most potent ligands [(±)-47, and (±)-38Ki = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding (S)-eutomers (Ki = 6.30 and 11.10 nM, respectively). The assessment of the effect in representative cytochromes (CYP3A4 and CYP2D6) demonstrated insignificant inhibitory activity, while in vitro experiments in three prostate cancer cells demonstrated that this pair of compounds exhibits a pronounced antimetastatic effect.
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