title: Application of the phosphoramidate ProTide approach to 4'-azidouridine confers sub-micromolar potency versus hepatitis C virus on an inactive nucleoside.
abstract: We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.
authors: Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
authors: Plinio
authors: P
authors: Perrone
authors: Giovanna M
authors: GM
authors: Luoni
authors: Mary Rose
authors: MR
authors: Kelleher
authors: Felice
authors: F
authors: Daverio
authors: Annette
authors: A
authors: Angell
authors: Sinead
authors: S
authors: Mulready
authors: Costantino
authors: C
authors: Congiatu
authors: Sonal
authors: S
authors: Rajyaguru
authors: Joseph A
authors: JA
authors: Martin
authors: Vincent
authors: V
authors: Levêque
authors: Sophie
authors: S
authors: Le Pogam
authors: Isabel
authors: I
authors: Najera
authors: Klaus
authors: K
authors: Klumpp
authors: David B
authors: DB
authors: Smith
authors: Christopher
authors: C
authors: McGuigan
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012093:Replicon; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C520345:4'-azidouridine; D000998:Antiviral Agents; D001386:Azides; D009943:Organophosphorus Compounds; D014529:Uridine