Structural Modification and Biological Evaluation of 2,8-Disubstituted Adenine and Its Nucleosides as A Adenosine Receptor Antagonists: Exploring the Roles of Ribose at Adenosine Receptors.

Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hAAR antagonist , we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hAAR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hAAR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine demonstrated the highest selectivity for hAAR ( = 5.0 ± 0.5 nM, / = 86) and effectively blocked cAMP production and restored IL-2 secretion in PBMCs. Favorable pharmacokinetic properties and a notable enhancement of anticancer effects in combination with an mAb immune checkpoint blockade were observed upon oral administration of . These findings establish as a viable immune-oncology therapeutic candidate.