Synthesis, evaluation of anti-HIV-1 and anti-HCV activity of novel 2′,3′-dideoxy-2′,2′-difluoro-4′-azanucleosides
2012
Martínez-Montero, Saúl | Fernández, Susana | Sanghvi, Yogesh S. | Theodorakis, Emmanuel A. | Detorio, Mervi A. | Mcbrayer, Tamara R. | Whitaker, Tony | Schinazi, Raymond F. | Gotor, Vicente | Ferrero Melgar, Miguel
A series of 2′,3′-dideoxy-2′,2′-difluoro-4′-azanucleosides of both pyrimidine and purine nucleobases were synthesized in an efficient manner starting from commercially available L-pyroglutamic acid via glycosylation of difluorinated pyrrolidine derivative 15. Several 4′-azanucleosides were prepared as a separable mixture of α- and β-anomers. The 6-chloropurine analogue was obtained as a mixture of N⁷ and N⁹ regioisomers and their structures were identified based on NOESY and HMBC spectral data. Among the 4′-azanucleosides tested as HIV-1 inhibitors in primary human lymphocytes, four compounds showed modest activity and the 5-fluorouracil analogue (18d) was found to be the most active compound (EC₅₀=36.9μM) in this series. None of the compounds synthesized in this study demonstrated anti-HCV activity.
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