2026-04-17T16:04:34Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2141752025-11-20T15:01:23Zcom_2072_1057col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Prieto Díaz, Rubén author Fojo Carballo, Hugo author Majellaro, Maria author Tandarić, Tana author Azuaje, Jhonny author Brea, José author Loza, María I. author Barbazán, Jorge author Salort, Glòria author Chotalia, Meera author Rodríguez Pampín, Iván author Mallo Abreu, Ana author Rita Paleo, M. author García Mera, Xerardo author Ciruela Alférez, Francisco author Gutiérrez de Terán, Hugo author Sotelo, Eddy author 2024-07-02T15:31:35Z 2024-07-02T15:31:35Z 2024-04-01 2024-06-17T13:56:10Z Antagonists of the A(2B) 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 A(2B)AR 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 (K-i < 100 nM) and outstanding selectivity for A(2B)AR. From these, five molecules corresponding to the new benzothiazole scaffold were below the K-i < 10 nM threshold, in addition to a novel dual A(2A)/A(2B) antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A(2B)AR. Two A(2B)AR selective antagonists and the dual A(2A)AR/A(2B)AR 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 A(2B)AR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A(2B)AR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A(2A)AR antagonism in the context of immune checkpoint inhibition. Càncer colorectal Medicaments antineoplàstics Colorectal cancer Antineoplastic agents Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents