Evaluation of novel phosphoramidate ProTides of the 2'-fluoro derivatives of a potent anti-varicella zoster virus bicyclic nucleoside analogue.
BACKGROUND
Recently, the synthesis and antiviral activity of a series of 2'-fluoro derivatives of the most potent anti-varicella zoster virus (VZV) agent reported to date, the bicyclic nucleoside analogue Cf1743, have been reported.


METHODS
Here, we present molecular modelling studies for the interaction of these compounds with VZV-encoded thymidine kinase (TK) and we report the synthesis of a series of phosphoramidate ProTides of these compounds designed to bypass the nucleoside kinase dependence of the parent nucleoside analogues.


RESULTS
The phosphoramidate prodrugs were equally effective as their parent compounds against VZV in cell culture, but lost antiviral potency against TK-deficient VZV strains.


CONCLUSIONS
ProTide-based kinase bypass is not successful in this case.
Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
Marco
M
Derudas
Maurizio
M
Quintiliani
Andrea
A
Brancale
Graciela
G
Andrei
Robert
R
Snoeck
Jan
J
Balzarini
Christopher
C
McGuigan
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D005461:Fluorine / Q000737:chemistry*; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D011741:Pyrimidine Nucleosides / Q000737:chemistry* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000737:chemistry / Q000378:metabolism
D000577:Amides; D000998:Antiviral Agents; C500967:Cf 1743; D010756:Phosphoric Acids; D011741:Pyrimidine Nucleosides; D005461:Fluorine; C011067:phosphoramidic acid; D013937:Thymidine Kinase