Design, Synthesis, and Biological Activity of L-1′-Homologated Adenosine Derivatives

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 mu M for PPAR gamma and 1.0 mu M for PPAR delta) were significantly improved in comparison with those of the JP-nucleoside compound 1 (11.9 and 2.7 mu M, respectively). In addition, the L-nucleosides showed more potent adiponectin-secretion-promoting activity than the n-nucleoside analogues.

Automated summary

In this study, L-nucleoside analogues were synthesized using computer-aided design and were found to exhibit enhanced adiponectin-secretion-promoting activity and improved PPAR binding activities compared to n-nucleoside analogues.