title: Synthesis of 2'-O,4'-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase.
abstract: The synthesis of 2'-O,4'-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2'-C-methyl or 5'-C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive hydrates prior to alkylation. The 2'-C-methyl- and 5'-C-methyl-modified bicyclic guanosines were evaluated, along with the known uracil-, cytosine-, adenine-, guanine-LNA and guanine-ENA nucleosides, as potential antiviral agents and found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay. Examination of the corresponding nucleoside triphosphates, however, against the purified HCV NS5B polymerase indicated that LNA-G and 2'-C-methyl-LNA-G are potent inhibitors of both 1b wild type and S282T mutant enzymes in vitro. Activity was further demonstrated for the LNA-G-triphosphate against HCV NS5B polymerase genotypes 1a, 2a, 3a and 4a. A phosphorylation by-pass prodrug strategy may be required to promote anti-HCV activity in the replicon assay.
authors.affiliation: Biology Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chapron
authors.affiliation: Peakdale Molecular Ltd., Chapel-en-le-Frith, Derbyshire SK23 0PG, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Glen
authors.affiliation: Biology Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: La Colla
authors.affiliation: CMC Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA. Electronic address: mayes.ben@idenix.com.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Mayes
authors.affiliation: Biology Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: McCarville
authors.affiliation: Peakdale Molecular Ltd., Chapel-en-le-Frith, Derbyshire SK23 0PG, UK. Electronic address: stephen.moore@peakdale.co.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: Moore
authors.affiliation: CMC Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
authors.forename: Adel
authors.initials: A
authors.lastname: Moussa
authors.affiliation: Peakdale Molecular Ltd., Chapel-en-le-Frith, Derbyshire SK23 0PG, UK.
authors.forename: Ruhul
authors.initials: R
authors.lastname: Sarkar
authors.affiliation: Biology Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Seifer
authors.affiliation: Biology Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Serra
authors.affiliation: CMC Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
authors.forename: Alistair
authors.initials: A
authors.lastname: Stewart
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D012263:Ribonucleosides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Bicyclic ribonucleosides; Counter current chromatography; HCV; LNA nucleosides; NS5B polymerase; Oxidation–Grignard