Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists

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dc.contributor.authorPrieto-Diaz, Ruben
dc.contributor.authorGonzalez-Gomez, Manuel
dc.contributor.authorFojo-Carballo, Hugo
dc.contributor.authorAzuaje, Jhonny
dc.contributor.authorEl Maatougui, Abdelaziz
dc.contributor.authorMajellaro, Maria
dc.contributor.authorLoza, Maria, I
dc.contributor.authorBrea, Jose
dc.contributor.authorFernandez-Duenas, Victor
dc.contributor.authorPaleo, M. Rita
dc.contributor.authorDiaz-Holguin, Alejandro
dc.contributor.authorGarcia-Pinel, Beatriz
dc.contributor.authorMallo-Abreu, Ana
dc.contributor.authorEstevez, Juan C.
dc.contributor.authorAndujar-Arias, Antonio
dc.contributor.authorGarcia-Mera, Xerardo
dc.contributor.authorGomez-Tourino, Iria
dc.contributor.authorCiruela, Francisco
dc.contributor.authorSalas, Cristian O.
dc.contributor.authorGutierrez-de-Teran, Hugo
dc.contributor.authorSotelo, Eddy
dc.date.accessioned2025-01-20T20:19:50Z
dc.date.available2025-01-20T20:19:50Z
dc.date.issued2023
dc.description.abstractThe modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di-and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.
dc.fuente.origenWOS
dc.identifier.doi10.1021/acs.jmedchem.2c01768
dc.identifier.eissn1520-4804
dc.identifier.issn0022-2623
dc.identifier.urihttps://doi.org/10.1021/acs.jmedchem.2c01768
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/92546
dc.identifier.wosidWOS:000899518100001
dc.issue.numero1
dc.language.isoen
dc.pagina.final912
dc.pagina.inicio890
dc.revistaJournal of medicinal chemistry
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleExploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists
dc.typeartículo
dc.volumen66
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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