2. Academic Validation
  3. Structure-Activity Relationships of Truncated 1'-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs

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

  • J Med Chem. 2023 Apr 13;66(7):4961-4978. doi: 10.1021/acs.jmedchem.2c02071.
Young Eum Hyun 1,  Seungchan An 1 2,  Minjae Kim 1,  In Guk Park 1 2,  Sanghee Yoon 3,  Hafiz Muhammad Ahmad Javaid 4,  Thi Ngoc Lan Vu 3,  Gyudong Kim 1 4,  Hongseok Choi 1,  Hyuk Woo Lee 5,  Minsoo Noh 1 2,  Joo Young Huh 4,  Sun Choi 3,  Hong-Rae Kim 6,  Lak Shin Jeong 1 5
Affiliations

Affiliations

  • 1 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
  • 2 Natural Products Research Institute, Seoul National University, Seoul 08826, Korea.
  • 3 Global AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 4 College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea.
  • 5 Future Medicine Co., Ltd., Seongnam 13449, Gyeonggi-do, Korea.
  • 6 Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02708, Korea.
PMID: 36967575 DOI: 10.1021/acs.jmedchem.2c02071
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.

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