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.
- 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: [email protected].
- 4. Peakdale Molecular Ltd., Chapel-en-le-Frith, Derbyshire SK23 0PG, UK. Electronic address: [email protected].
- 5. CMC Department, Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA.
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.