First example of phosphoramidate approach applied to a 4'-substituted purine nucleoside (4'-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus.
We report on the synthesis of the anti hepatitis C virus (HCV) agent 4'-azidoadenosine (1) and the application of the phosphoramidate ProTide technology to this nucleoside. The synthesis of 1 was achieved through an epoxide intermediate followed by regio- and stereoselective ring opening by azidotrimethylsilane in the presence of a Lewis acid. Compound 1 did not inhibit HCV replication in cell culture at concentrations up to 0.1 mM. However, a submicromolar active agent could be derived from 1 by the application of the ProTide technology. All the phosphoramidates prepared were L-alanine derivatives with variations in the aryl moiety and in the ester part of the amino acid. The benzyl ester and the l-naphthyl phosphate (18) had the best activity in replicon assay. Phosphoramidates (18-21) achieved a significant improvement in antiviral potency over the parent nucleoside (1) with no increase in cytotoxicity.
Perrone
Plinio
P
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
Daverio
Felice
F
Valente
Rocco
R
Rajyaguru
Sonal
S
Martin
Joseph A
JA
Lévêque
Vincent
V
Le Pogam
Sophie
S
Najera
Isabel
I
Klumpp
Klaus
K
Smith
David B
DB
McGuigan
Christopher
C
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D012093:Replicon; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
C524715:4'-azidoadenosine; D000998:Antiviral Agents; D001386:Azides; D009943:Organophosphorus Compounds; D000241:Adenosine