Selenium bioisosteric replacement of adenosine derivatives promoting adiponectin secretion increases the binding affinity to peroxisome proliferator-activated receptor δ

Abstract N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide (1a, IB-MECA) exhibited polypharmacological characteristics targeting A3 adenosine receptor (AR), peroxisome proliferator-activated receptor (PPAR) γ, and PPARδ, simultaneously. The bioisosteric replacement of oxygen in 4′-oxoadenosines with selenium significantly increased the PPARδ-binding activity. 2-Chloro-N6-(3-iodobenzyl)-4′-selenoadenosine-5′-N-methyluronamide (3e) and related 4′-selenoadenosine derivatives significantly enhanced adiponectin biosynthesis during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). The PPARδ-binding affinity, but not the A3 AR binding affinity, of 4′-selenoadenosine derivatives correlated with their adiponectin secretion stimulation. Compared with the sugar ring of 4′-oxoadenosine, that of 4′-selenoadenosine was more favorable in forming the South sugar conformation. In the molecular docking simulation, the South sugar conformation of compound 3e formed additional hydrogen bonds inside the PPARδ ligand-binding pocket compared with the North conformation. Therefore, the sugar conformation of 4′-selenoadenosine PPAR modulators affects the ligand binding affinity against PPARδ.