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

Mai Nguyen; Seungchan An; Yen Nguyen; Young Eum Hyun; Hongseok Choi; Linh Pham; Jung-Ae Kim; Minsoo Noh; Gyudong Kim; Lak Shin Jeong

doi:10.1021/acsmedchemlett.2c00159

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. eCollection 2022 Jul 14.

Authors

Mai Nguyen¹, Seungchan An^{2

3}, Yen Nguyen¹, Young Eum Hyun², Hongseok Choi², Linh Pham¹, Jung-Ae Kim⁴, Minsoo Noh^{2

3}, Gyudong Kim¹, Lak Shin Jeong²

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.

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.