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

Christopher Chapron; Rebecca Glen; Massimiliano La Colla; Benjamin A Mayes; Joseph F McCarville; Stephen Moore; Adel Moussa; Ruhul Sarkar; Maria Seifer; Ilaria Serra; Alistair Stewart

doi:10.1016/j.bmcl.2014.04.050

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. Epub 2014 Apr 19.

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.

MeSH terms

Enzyme Activation / drug effects
Hepacivirus / drug effects
Hepacivirus / enzymology*
Molecular Structure
Nucleic Acid Synthesis Inhibitors / chemical synthesis*
Nucleic Acid Synthesis Inhibitors / pharmacology*
Ribonucleosides / chemical synthesis*
Ribonucleosides / chemistry
Ribonucleosides / pharmacology*
Viral Nonstructural Proteins / antagonists & inhibitors*
Viral Nonstructural Proteins / metabolism*

Substances

Nucleic Acid Synthesis Inhibitors
Ribonucleosides
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus