Synthesis and Biological Evaluation of 5′-Deoxy-adenosine\nDerivatives as A<sub>3</sub> Adenosine Receptor Ligands

The\nA<sub>3</sub> Adenosine Receptor (A<sub>3</sub>AR) is an important\ntherapeutic target due to its role in inflammation and immune response\nregulation. Herein, we synthesized and evaluated 5′-deoxy-adenosine\nderivatives with oxygen at the 4′-position, comparing them\nto previously studied 4′-thionucleosides. Compound <b>1h</b> exhibited the highest binding affinity (<i>K</i><sub>i</sub> = 5.9 ± 1.1 nM), consistent with the trend observed in the\n4′-thionucleosides. Notably, the 5′-deoxy-adenosine\nderivatives demonstrated enhanced agonistic activity. Docking studies\nwith compound <b>1h</b> revealed a shift in binding mode when\noxygen replaced sulfur at the 4′-position. The compounds retained\nstrong interactions with critical residues, such as Thr94, even without\na hydrogen bond donor at the 5′-position. These results explain\nthe increased agonistic effect observed when the ring heteroatom was\nchanged from sulfur to oxygen.