Anchimerically Activatable Antiviral ProTides

This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2′-C-β-methylguanosine as an inhibitor of dengue virus 2 (DENV-2). The proTide incorporates a chemically cleavable 2-(methylthio)­ethyl moiety and a HINT1 hydrolyzable tryptamine phosphoramidate. In...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2017-09, Vol.8 (9), p.958-962
Main Authors: Okon, Aniekan, Matos de Souza, Marcos Romário, Shah, Rachit, Amorim, Raquel, da Costa, Luciana Jesus, Wagner, Carston R
Format: Article
Language:English
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Letter
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Summary:This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2′-C-β-methylguanosine as an inhibitor of dengue virus 2 (DENV-2). The proTide incorporates a chemically cleavable 2-(methylthio)­ethyl moiety and a HINT1 hydrolyzable tryptamine phosphoramidate. Inhibition of DENV-2 replication by proTide 6 was 5-fold greater than the parent nucleoside while displaying no apparent cytotoxicity. Furthermore, we demonstrate with a HINT1 inhibitor that the anti DENV-2 activity of the proTide correlates with the activity of HINT1. Taken together, these results demonstrate that a phosphoramidate based pronucleotide that undergoes an initial nonenzymatic activation step based on anchimeric assistance followed by P–N bond cleavage by HINT1 can be prepared.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.7b00277