Design, synthesis, and biological evaluation of 5ʹ-deoxy (N)-methanocarbanucleoside derivatives as A3 adenosine receptor ligands

Abstract

Based on the potent and selective antagonism exhibited by truncated North (N)-methanocarba adenosine analogs, we synthesized a series of 5ʹ-deoxy (N)-methanocarba nucleosides to explore their structure–activity relationships (SAR). The stereoselective synthesis of the North cyclopropyl-fused alcohol was achieved from d-ribose using ring-closing metathesis, oxidative rearrangement, and cyclopropanation as key steps. Mitsunobu reactions were employed to condense nucleobases with glycosyl donors, followed by N⁶ functionalization with various amines. Despite their innovative design, all synthesized analogs exhibited lower binding affinity compared to the 4ʹ-thio series and fully truncated (N)-methanocarba adenosine. Docking studies revealed that the 4ʹ-methyl group of the rigid North conformational sugar introduces steric clashes, which likely contribute to the reduced affinity. These findings underscore the critical role of sugar conformation and steric effects in receptor interactions, providing valuable insights for the development of potent and selective A₃AR ligands.