Design, synthesis and biological evaluation of truncated 1'-homologated 4'-selenonucleosides as PPARγ/δ dual modulators.

This study explores the synthesis and evaluation of truncated 1'-homologated 4'-selenonucleosides as dual modulators of PPARγ and PPARδ. Starting with d-lyxose, a 4'-selenosugar was synthesized and condensed with a nucleobase via an S2 reaction, followed by modifications at the C2- and N-positions, yielding compounds 3a-l. Structure-activity trend analysis identified compound 3h, featuring 2-chloro and N-3-iodobenzylamine substituents, as a potent PPARγ partial agonist and PPARδ antagonist (PPARγ K = 2.8 μM, PPARδ K = 43 nM). This compound significantly enhanced adiponectin production and promoted adipogenic differentiation in hBM-MSCs. The 4'-seleno substitution preserved ligand functionality while enhancing binding affinity and pharmacological efficacy. In silico docking studies supported these binding affinities, demonstrating optimal binding poses for 3h at both PPARγ and PPARδ. These findings underscore the potential of 4'-selenonucleosides as therapeutic agents for metabolic disorders associated with hypoadiponectinemia, meriting further investigation and clinical development.