Structure–Activity Relationships of Truncated 1′-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs

Peroxisome proliferator-activated receptors (PPARs) are
associated
with the regulation of metabolic homeostasis. Based on a previous
report that 1′-homologated 4′-thionucleoside acts as
a dual PPARγ/δ modulator, carbocyclic nucleosides 2–5 with various sugar conformations were
synthesized to determine whether sugar puckering affects binding to
PPARs. (S)-conformer 2 was synthesized
using Charette asymmetric cyclopropanation, whereas (N)-conformer 3 was synthesized using stereoselective
Simmons–Smith cyclopropanation. All synthesized nucleosides
did not exhibit binding affinity to PPARα but exhibited significant
binding affinities to PPARγ/δ. The binding affinity of
final nucleosides to PPARγ did not differ significantly based
on their conformation, but their affinity to PPARδ depended
greatly on their conformation, correlated with adiponectin production.
(N)-conformer 3h was discovered to be
the most potent PPARδ antagonist with good adiponectin production,
which exhibited the most effective activity in inhibiting the mRNA
levels of LPS-induced IL-1β expression in RAW 264.7 macrophages,
implicating its anti-inflammatory activity.