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A series of 7-deazaneplanocin A (7-DNPA, 2) analogues were synthesized and evaluated for in vitro antiviral activity against HBV and HCV. The syntheses of target carbocyclic nucleosides were accomplished via a convergent procedure. 7-Substitutions were introduced by using 7-substituted-7-deaza heterocyclic base precursors (F, Cl, Br, and I) or via substitution reactions after the synthesis of the carbocyclic nucleosides. Among the synthesized compounds, 2, 13−15, 24, and 27exhibited significant anti-HCV activity (EC50ranged from 1.8 to 20.1 μM) and compounds 2, 15, 22, and 24demonstrated moderate to potent anti-HBV activity (EC50= 0.3−3.3 μM). In addition, compound 24also showed activity against lamivudine- and adefovir-associated HBV mutants. [ABSTRACT FROM AUTHOR]

Introducing 2‘-fluoro substitution on the 2‘,3‘-double bond in carbocyclic nucleosides has provided biologically interesting compounds with potent anti-HIV activity. As an extension of our previous works in the discovery of anti-HIV agents, d- and l-2‘,3‘-unsaturated 3‘-fluoro carbocyclic nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. Among the synthesized l-series nucleosides, compounds 18, 19, 26and 28exhibited moderate antiviral activity (EC507.1 M, 6.4 M, 10.3 M, and 20.7 M, respectively), while among the d-series, the guanosine analogue (35, d-3‘-F-C-d4G) exhibited the most potent anti-HIV activity (EC500.4 M, EC902.8 M). However, the guanosine analogue 35was cross-resistant to the lamivudine-resistant variants (HIV-1M184V). Molecular modeling studies suggest that hydrophobic interaction as well as hydrogen-bonding stabilize the binding of compound 35in the active site of wild type HIV reverse transcriptase (HIV-RT). In the case of l-nucleosides, these two effects are opposite which results in a loss of binding affinity. According to the molecular modeling studies, cross-resistance of d-3‘-F-C-d4G (35) to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184Vinteraction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of the d-guanine derivative 35. [ABSTRACT FROM AUTHOR]