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

Prieto Díaz, RubénGonzález Gómez, ManuelFojo Carballo, HugoAzuaje, JhonnyEl Maatougui, AbdelazizMajellaro, MaríaLoza García, María IsabelBrea Floriani, José ManuelFernández Dueñas, VíctorPaleo Pillado, María RitaDíaz Holguín, AlejandroGarcía Pinel, BeatrizMallo Abreu, AnaEstévez, Juan C.Andújar Arias, AntonioGarcía Mera, XerardoGómez Tourino, IriaCiruela, FranciscoSalas, Cristian O.Gutiérrez de Terán, HugoSotelo Pérez, Eddy2024-02-022024-02-022022-12-14Prieto-Díaz, R., González-Gómez, M., Fojo-Carballo, H., Azuaje, J., El Maatougui, A., Majellaro, M., Loza, M.I., Brea, J., Fernández-Dueñas, V., Paleo, M.R., Díaz-Holguín, A., Garcia-Pinel, B., Mallo-Abreu, A., Estévez, J.C., Andújar-Arias, A., García-Mera, X., Gomez-Tourino, I., Ciruela, F., Salas, C.O., Gutiérrez-de-Terán, H., and Sotelo, E.(2023). Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists. Journal of Medicinal Chemistry. 66 (1), 890-9120022-2623http://hdl.handle.net/10347/32239The 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 halogensize-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.engThis publication is licensed under CC-BY 4.0.http://creativecommons.org/licenses/by/4.0/AdenosineHalogenationCancer therapy2306 Química orgánicaExploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonistsjournal article10.1021/acs.jmedchem.2c017681520-4804open access