Design, Synthesis, and Biological Activity of l-1'-Homologated Adenosine Derivatives

  • ACS Med Chem Lett. 2022 Jun 17;13(7):1131-1136. doi: 10.1021/acsmedchemlett.2c00159.
Mai Nguyen  1 ,  Seungchan An  2  3 ,  Yen Nguyen  1 ,  Young Eum Hyun  2 ,  Hongseok Choi  2 ,  Linh Pham  1 ,  Jung-Ae Kim  4 ,  Minsoo Noh  2  3 ,  Gyudong Kim  1 ,  Lak Shin Jeong  2
Affiliations
  • 1. College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea.
  • 2. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
  • 3. Natural Products Research Institute, Seoul National University, Seoul 08826, Korea.
  • 4. College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
PMID: 35859875 DOI: 10.1021/acsmedchemlett.2c00159
Abstract

On the basis of the previously reported polypharmacological profile of truncated d-1'-homologated adenosine derivatives [J. Med. Chem.2020, 63, 16012], the l-nucleoside analogues were synthesized using computer-aided design and evaluated for biological activity. The target molecules were synthesized from d-ribose via the key intramolecular cyclization of the monotosylate and Mitsunobu condensation. The Peroxisome Proliferator-activated Receptor (PPAR) binding activities of l-nucleoside analogue 2d (K i = 4.3 μM for PPARγ and 1.0 μM for PPARδ) were significantly improved in comparison with those of the d-nucleoside compound 1 (11.9 and 2.7 μM, respectively). In addition, the l-nucleosides showed more potent adiponectin-secretion-promoting activity than the d-nucleoside analogues.