Synthesis and Anti-Hepatitis B Activities of 3′-Fluoro-2′-Substituted Apionucleosides

Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2′-hydroxy- and 2′-hydroxy...

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Detalles Bibliográficos
Autores principales: Holan, Martin, Tucker, Kathryn, Dyatkina, Natalia, Liu, Hong, Kinkade, April, Wang, Guangyi, Jin, Zhinan, Prhavc, Marija
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025269/
https://www.ncbi.nlm.nih.gov/pubmed/35458620
http://dx.doi.org/10.3390/molecules27082413
Descripción
Sumario:Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2′-hydroxy- and 2′-hydroxymethyl-apionucleosides, 4 and 5, corresponding triphosphates and phosphoramidate prodrugs. Triphosphate 38 of 2′-hydroxymethyl-apionucleoside 5 exhibited potent inhibition of HBV polymerase with an IC(50) value of 120 nM. In an HBV cell-based assay, the phosphoramidate prodrug 39 demonstrated potent activity with an EC(50) value of 7.8 nM.