Anchimerically Activatable Antiviral ProTides

摘要

src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/amclct/2017/amclct.2017.8.issue-9/acsmedchemlett.7b00277/20170908/images/medium/ml-2017-00277y_0006.gif">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.