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In order to study structure-activity relationships among the derivatives and congeners of 5′,9-anhydro-3-(β-D-ribofuranosyl)xanthine for anti-hepatitis C virus activity, a series of 5′,9-anhydro-purine-isonucleosides with a substituent (s) at 6- or/and 8-position of the purine moiety were synthesized, and their anti-hepatitis C virus activity and cytotoxicity were evaluated and discussed. [ABSTRACT FROM AUTHOR]

Abstract: The 3′,5′-cyclic phosphate prodrug 9-[β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylribofuranosyl]-2-amino-6-ethoxypurine, PSI-352938 1, has demonstrated promising anti-HCV efficacy in vitro and in human clinical trials. A structure–activity relationship study of the nucleoside 3′,5′-cyclic phosphate series of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylribofuranosyl nucleoside prodrugs was undertaken and the anti-HCV activity and in vitro safety profile were assessed. Cycloalkyl 3′,5′-cyclic phosphate prodrugs were shown to be significantly more potent as inhibitors of HCV replication than branched and straight chain alkyl 3′,5′-cyclic phosphate prodrugs. No cytotoxicity and mitochondrial toxicity for prodrugs 12, 13 and 19 were observed at concentrations up to 100μm in vitro. Cycloalkyl esters of 3′,5′-cyclic phosphate nucleotide prodrugs demonstrated the ability to produce high levels of active triphosphate in clone-A cells and primary human hepatocytes. Compounds 12, 13 and 19 also demonstrated the ability to effectively deliver in vivo high levels of active nucleoside phosphates to rat liver. [Copyright &y& Elsevier]

A new approach to the synthesis of 2′,3′-didehydro-2′,3′-dideoxynucleosides was described in excellent yield through unusual olefin formation by PhSe-F trans -elimination. [ABSTRACT FROM AUTHOR]

Novel 4′-substituted β- d -2′-deoxy-2′-α-fluoro (2′d2′F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4′-substitution onto 2′d2′F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4′-substitution and not readily predictable. Combining the most potent and selective 4′-groups from N -nucleoside analogs onto a 2′d2′F C -nucleoside analog resulted in the identification of β- d -2′-deoxy-2′-α-fluoro-4′-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel 2′-deoxy-2′-α-fluoro-2′-β-C-methyl 3′,5′-cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10–100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure–activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats. These studies ultimately led to the selection of the clinical development candidate 24a (PSI-352938). [ABSTRACT FROM AUTHOR]

Novel racemic, D- and L-β-dioxolane N4 -hydroxycylosine nucleosides have been synthesized and evaluated for their activity against hepatitis B virus. None of the synthesized nucleosides demonstrated selective anti-HBV activity. [ABSTRACT FROM AUTHOR]