1160287-69-3Relevant academic research and scientific papers
Synthesis of 2′-O,4′-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase
Chapron, Christopher,Glen, Rebecca,La Colla, Massimiliano,Mayes, Benjamin A.,McCarville, Joseph F.,Moore, Stephen,Moussa, Adel,Sarkar, Ruhul,Seifer, Maria,Serra, Ilaria,Stewart, Alistair
, p. 2699 - 2702 (2014/06/09)
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.
