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.
Bibliographical noteFunding Information:
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2022R1A6A1A03046247), the Mid-career Researcher Programs (NRF-2021R1A2B5B02001544 and NRF-2020R1A2C2101636) and Bio & Medical Technology Development Program (NRF-2022M3E5F3080873), and the Ewha Womans University Research Grant of 2021.
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