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Conformationally restricted 2′-spironucleosidesand theirprodrugs were synthesized as potential anti-HCV agents. Although thereplicon activity of the new agents containing pyrimidine bases wasmodest, the triphosphate of a 2′-oxetane cytidine analoguedemonstrated potent intrinsic biochemical activity against the NS5Bpolymerase, with IC50= 8.48 μM. Activity againstNS5B bearing the S282T mutation was reduced. Phosphoramidate prodrugsof a 2′-oxetane 2-amino-6-O-methyl-purinenucleoside demonstrated potent anti-HCV activity in vitro, and thecorresponding triphosphate retained similar potent activity againstboth wild-type and S282T HCV NS5B polymerase. [ABSTRACT FROM AUTHOR]

In order to support bioanalytical LC/MS method development and plasma sample analysis in preclinical and clinical studies of the anti-hepatitis C-virus nucleotides, PSI-7977 and PSI-352938, the corresponding stable isotope labeled forms were prepared. These labeled compounds were prepared by addition reaction of the freshly prepared Grignard reagent 13CD3MgI to the corresponding 2 ′-ketone nucleosides followed by fluorination of the resulting carbinol with DAST. As expected, these 2 ′-C-(trideuterated-13C-methyl) nucleotide prodrugs showed similar anti-HCV activity to that of the corresponding unlabeled ones. [ABSTRACT FROM AUTHOR]

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]

Synthesis of ring-expanded analogs of the natural compound, oxetanocin is described. The starting material for the synthesis of the series, 4–7, was d-glucosamine and introduction of the base moiety was done through the stereochemically appropriate epoxide. For the enantiomeric series, 8–11, the starting material was d-glucose and preparation of the key intermediate involved a rearrangement reaction. The structures of the target molecules were established by NMR, HRMS, optical rotation and UV data. Single-crystal X-ray data confirmed the enantiomeric structural assignments. [Copyright &y& Elsevier]

Abstract: 5′,9-Anhydro-3-(β-d-ribofuranosyl)xanthine and 3,5′-anhydro-xanthosine were prepared as potential anti-hepatitis C virus (HCV) agents from uridine and xanthosine, respectively. [Copyright &y& Elsevier]

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]

Novel racemic 5′-C-methyl-1′,3′-dioxolan-4′-yl nucleosides were synthesized from the key intermediate, 2-benzoyloxymethyl-4-oxo-5-C-methyl-1,3-dioxolane, which was prepared from racemic lactic acid. [Copyright &y& Elsevier]