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

Young Eum Hyun, Seungchan An, Minjae Kim, In Guk Park, Sanghee Yoon, Hafiz Muhammad Ahmad Javaid, Thi Ngoc Lan Vu, Gyudong Kim, Hongseok Choi, Hyuk Woo Lee, Minsoo Noh, Joo Young Huh, Sun Choi, Hong Rae Kim, Lak Shin Jeong

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4961-4978
Number of pages18
JournalJournal of Medicinal Chemistry
Volume66
Issue number7
DOIs
StatePublished - 13 Apr 2023

Bibliographical note

Funding 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.

Publisher Copyright:
© 2023 American Chemical Society.

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