4'-Thionucleosides as adenosine A3 receptor ligands: a medicinal chemistry perspective

초록

The adenosine A(3) receptor (A(3)AR) is recognized as a potential therapeutic target across multiple human pathologies; however, the development of selective orthosteric ligands remains challenging due to receptor subtype conservation and species-dependent pharmacology. Among nucleoside-derived chemotypes, 4'-thionucleosides, generated by bioisosteric replacement of the ribose endocyclic oxygen with sulfur, constitute a synthetically accessible scaffold for modulating A(3)AR activity. This review summarizes synthetic methodologies that have enabled systematic diversification of the 4'-thio chemotype, including beta-selective N-glycosylation and de novo cyclization strategies, and analyzes structure-activity relationships (SAR) associated with modifications at the N6, C2, and 5' positions, as well as ribose truncation. These structural variations have been correlated with changes in binding affinity, subtype selectivity, and intrinsic efficacy, supporting the utility of the 4'-thio scaffold in generating distinct pharmacological profiles. The recent availability of cryo-electron microscopy structures of human A(3)AR, including active agonist-bound states and, more recently, an inactive antagonist-bound conformation, provides a structural context for interpretation of established SAR trends and may facilitate future structure-guided and modeling-informed ligand optimization.

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