RT Journal Article
T1 Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists
A1 Prieto Díaz, Rubén
A1 González Gómez, Manuel
A1 Fojo Carballo, Hugo
A1 Azuaje, Jhonny
A1 El Maatougui, Abdelaziz
A1 Majellaro, María
A1 Loza García, María Isabel
A1 Brea Floriani, José Manuel
A1 Fernández Dueñas, Víctor
A1 Paleo Pillado, María Rita
A1 Díaz Holguín, Alejandro
A1 García Pinel, Beatriz
A1 Mallo Abreu, Ana
A1 Estévez, Juan C.
A1 Andújar Arias, Antonio
A1 García Mera, Xerardo
A1 Gómez Tourino, Iria
A1 Ciruela, Francisco
A1 Salas, Cristian O.
A1 Gutiérrez de Terán, Hugo
A1 Sotelo Pérez, Eddy
K1 Adenosine
K1 Halogenation
K1 Cancer therapy
AB The 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.
PB ACS Publications
SN 0022-2623
YR 2022
FD 2022-12-14
LK http://hdl.handle.net/10347/32239
UL http://hdl.handle.net/10347/32239
LA eng
NO Prieto-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), 890-912
NO This work was financially supported by the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government (grant: ED431B 2020/43), Centro Singular de Investigación de Galicia accreditation 2019-2022 (ED431G 2019/03), the European Regional Development Fund (ERDF), Ministerio de Ciencia e Innovación − Agencia Estatal de Investigación-FEDER-UE (PID2020-118511RB-I00 and PID2021-124010OB-100). Additional support from the Swedish strategic research program eSSENCE, the Swedish Cancer Society (#CAN 2018/451), and The Cancer Research Fundations of Radiumhemmet (#181183) is acknowledged.The computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC).We thank Centres de Recerca de Catalunya (CERCA) Programme/Generalitat de Catalunya for IDIBELL institutional support, Xunta de Galicia (ED431C 2018/21 and ED431G 2019/02), and European Regional Development Fund (ERDF) in the frame of the Recovery Assistance for Cohesion and the Territories of Europe (REACT-EU) funds.This research program has been developed in the frame of the European COST action ERNEST (CA 18133). 
DS Minerva
RD 30 abr 2026