Anchimerically Activatable Antiviral ProTides

作者：Okon Aniekan; Matos de Souza Marcos Romario; Shah Rachit; Amorim Raquel; da Costa Luciana Jesus; Wagner Carston R^*

来源：ACS Medicinal Chemistry Letters, 2017, 8(9): 958-962.

DOI：10.1021/acsmedchemlett.7b00277

• Phosphoramidate
• pronucleotide
• Dengue virus
• antiviral

This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2'-C-beta-methylguanosine as an inhibitor of dengue virus 2 (DENV-2). The proTide incorporates a chemically cleavable 2-(methylthio)ethyl moiety and a HINT! 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 HINT I 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.

• 出版日期2017-9