2. Academic Validation
  3. Synthesis of 2'-O,4'-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase

Synthesis of 2'-O,4'-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase

  • Bioorg Med Chem Lett. 2014 Jun 15;24(12):2699-702. doi: 10.1016/j.bmcl.2014.04.050.
Christopher Chapron 1,  Rebecca Glen 2,  Massimiliano La Colla 1,  Benjamin A Mayes 3,  Joseph F McCarville 1,  Stephen Moore 4,  Adel Moussa 5,  Ruhul Sarkar 2,  Maria Seifer 1,  Ilaria Serra 1,  Alistair Stewart 5
Affiliations

Affiliations

  • 1 Biology Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
  • 2 Peakdale Molecular Ltd., Chapel-en-le-Frith, Derbyshire SK23 0PG, UK.
  • 3 CMC Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA. Electronic address: mayes.ben@idenix.com.
  • 4 Peakdale Molecular Ltd., Chapel-en-le-Frith, Derbyshire SK23 0PG, UK. Electronic address: stephen.moore@peakdale.co.uk.
  • 5 CMC Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
PMID: 24815510 DOI: 10.1016/j.bmcl.2014.04.050
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.

Keywords

Bicyclic ribonucleosides; Counter current chromatography; HCV; LNA nucleosides; NS5B polymerase; Oxidation–Grignard.

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