Synthesis and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5′-triphosphates

Thirty novel α- and β-d-2′-deoxy-2′-fluoro-2′-C-methyl-7-deazapurine nucleoside analogs were synthesized and evaluated for in vitro antiviral activity. Several α- and β-7-deazapurine nucleoside analogs exhibited modest anti-HCV activity and cytotoxicity. Four synthesized 7-deazapurine nucleoside phosphoramidate prodrugs (18–21) showed no anti-HCV activity, whereas the nucleoside triphosphates (22–24) demonstrated potent inhibitory effects against both wild-type and S282T mutant HCV polymerases. Cellular pharmacology studies in Huh-7 cells revealed that the 5′-triphosphates were not formed at significant levels from either the nucleoside or the phosphoramidate prodrugs, indicating that insufficient phosphorylation was responsible for the lack of anti-HCV activity. Evaluation of anti-HIV-1 activity revealed that an unusual α-form of 7-carbomethoxyvinyl substituted nucleoside (10) had good anti-HIV-1 activity (EC50 = 0.71 ± 0.25 μM; EC90 = 9.5 ± 3.3 μM) with no observed cytotoxicity up to 100 μM in four different cell lines.

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