{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kim G"],"funding":["Intramural NIH HHS","National Institute of Diabetes and Digestive and Kidney Diseases","National Research Foundation of Korea"],"pagination":["12249-12265"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10896643"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["66(17)"],"pubmed_abstract":["Based on hA<sub>2A</sub>AR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA<sub>2A</sub>AR agonists into antagonists while maintaining affinity toward hA<sub>3</sub>AR. The final compounds of 2,8-disubstituted-<i>N</i><sup>6</sup>-substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled regioselective cross-coupling reaction. All tested compounds completely antagonized hA<sub>2A</sub>AR, including <b>5d</b> with the highest affinity (<i>K</i><sub>i,A<sub>2A</sub></sub> = 7.7 ± 0.5 nM). The hA<sub>2A</sub>AR-<b>5d</b> X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conformational changes. However, the C8-substituted compounds still antagonized hA<sub>3</sub>AR. Structural SAR features and docking studies supported different binding modes at A<sub>2A</sub>AR and A<sub>3</sub>AR, elucidating pharmacophores for receptor activation and selectivity. Favorable pharmacokinetics were demonstrated, in which <b>5d</b> displayed high oral absorption, moderate half-life, and bioavailability. Also, <b>5d</b> significantly improved the antitumor effect of anti-PD-L1 <i>in vivo</i>. Overall, this study suggests that the novel dual A<sub>2A</sub>AR/A<sub>3</sub>AR nucleoside antagonists would be promising drug candidates for immune-oncology."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Structure-Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A&lt;sub&gt;2A&lt;/sub&gt;/A&lt;sub&gt;3&lt;/sub&gt; Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity."],"pmcid":["PMC10896643"],"funding_grant_id":["NRF-2021R1A2B5B0200154413","Z01 DK031117","2021M3E5E308084321","NRF-2022R1A6A1A0304624712","ZIADK031117","ZIA DK031117"],"pubmed_authors":["Lee SK","Kim G","Lee CS","Gao ZG","Jeong LS","Hou X","Yu J","Choi JR","Lee G","Lee HW","Shin H","Qu S","Ji S","Jarhad DB","Byun WS","Jacobson KA","Warnick E","Kim JY","Hyun YE"],"additional_accession":[]},"is_claimable":false,"name":"Structure-Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A&lt;sub&gt;2A&lt;/sub&gt;/A&lt;sub&gt;3&lt;/sub&gt; Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity.","description":"Based on hA<sub>2A</sub>AR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA<sub>2A</sub>AR agonists into antagonists while maintaining affinity toward hA<sub>3</sub>AR. The final compounds of 2,8-disubstituted-<i>N</i><sup>6</sup>-substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled regioselective cross-coupling reaction. All tested compounds completely antagonized hA<sub>2A</sub>AR, including <b>5d</b> with the highest affinity (<i>K</i><sub>i,A<sub>2A</sub></sub> = 7.7 ± 0.5 nM). The hA<sub>2A</sub>AR-<b>5d</b> X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conformational changes. However, the C8-substituted compounds still antagonized hA<sub>3</sub>AR. Structural SAR features and docking studies supported different binding modes at A<sub>2A</sub>AR and A<sub>3</sub>AR, elucidating pharmacophores for receptor activation and selectivity. Favorable pharmacokinetics were demonstrated, in which <b>5d</b> displayed high oral absorption, moderate half-life, and bioavailability. Also, <b>5d</b> significantly improved the antitumor effect of anti-PD-L1 <i>in vivo</i>. Overall, this study suggests that the novel dual A<sub>2A</sub>AR/A<sub>3</sub>AR nucleoside antagonists would be promising drug candidates for immune-oncology.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Sep","modification":"2026-06-02T04:58:01.186Z","creation":"2025-04-04T02:04:56.95Z"},"accession":"S-EPMC10896643","cross_references":{"pubmed":["37603705"],"doi":["10.1021/acs.jmedchem.3c00806"]}}