Synthesis and Biological Activity of 7-Deaza-7-ethynyl-2′-deoxy-2′-fluoro-2′-C-methyladenosine and its 2′-C-Methyl-ribo Analogue

Abstract In our search for improved therapeutic agents against HCV we synthesized 7-deaza-7-ethynyl-2′-C-methyladenosine (1) and its 2′-deoxy-2′-fluoro analogue 2. The corresponding nucleoside triphosphates were efficient chain terminators of the HCV NS5b polymerase with IC50's of 0.75 µM and 0...

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Bibliographic Details
Published in:Nucleic Acids Symposium Series 2008, Vol.52 (1), p.643-644
Main Authors: Prhavc, Marija, Dyatkina, Natalia, Keicher, Jesse, Liehr, Sebastian, Koo-McCoy, Samantha, Latour, Derek, Fung, Kevin, Dunlop, Kevin, Pouliot, Jeffrey, Wang, Ting, Li, Wenbao, Lou, Lillian, Roberts, Christopher, Griffith, Ronald
Format: Article
Language:English
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Summary:Abstract In our search for improved therapeutic agents against HCV we synthesized 7-deaza-7-ethynyl-2′-C-methyladenosine (1) and its 2′-deoxy-2′-fluoro analogue 2. The corresponding nucleoside triphosphates were efficient chain terminators of the HCV NS5b polymerase with IC50's of 0.75 µM and 0.4 µM respectively. However, only the ribo-nucleoside 1 exhibited activity in a Huh7 cell based replicon assay with an EC50 of 0.09 µM. In order to overcome the lack of activity of the fluoro analogue 2 we synthesised several phosphoroamidate prodrugs.
ISSN:0261-3166
1746-8272
DOI:10.1093/nass/nrn325