Synthesis and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleosides, their phosphoramidate
Junxing Shi1, Longhu Zhou, Hongwang Zhang
1RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA.
Abstract:
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 (EC(50)=0.71±0.25 microM; EC(90)=9.5±3.3 microM) with no observed cytotoxicity up to 100 microM in four different cell lines.
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