Synthesis and Biological Evaluation of 5′-Deoxy-adenosine Derivatives as A3 Adenosine Receptor Ligands

The A3 Adenosine Receptor (A3AR) is an important therapeutic target due to its role in inflammation and immune response regulation. Herein, we synthesized and evaluated 5′-deoxy-adenosine derivatives with oxygen at the 4′-position, comparing them to previously studied 4′-thionucleosides. Compound 1h exhibited the highest binding affinity (Ki = 5.9 ± 1.1 nM), consistent with the trend observed in the 4′-thionucleosides. Notably, the 5′-deoxy-adenosine derivatives demonstrated enhanced agonistic activity. Docking studies with compound 1h revealed a shift in binding mode when oxygen replaced sulfur at the 4′-position. The compounds retained strong interactions with critical residues, such as Thr94, even without a hydrogen bond donor at the 5′-position. These results explain the increased agonistic effect observed when the ring heteroatom was changed from sulfur to oxygen.