title: Bicyclic nucleoside inhibitors of varicella-zoster virus modified on the sugar moiety: 3' and 5' derivatives.
abstract: Bicyclic furanopyrimidine nucleoside analogues (BCNAs) have been previously reported as potent and selective anti-varicella-zoster virus (VZV) agents. Few modifications on the sugar moiety have been considered so far but some of them have shown interesting activity against human cytomegalovirus (HCMV) while losing activity against VZV. In addition, recent work has led to an entirely new series of anti-HCMV bicyclic furopyrimidine agents, acting through a non-nucleoside mechanism. In order to further investigate structure-activity relationship studies on the sugar moiety, some 3'- and 5'-chloro derivatives and 5'-deoxygenated derivatives have been synthesized. The lack of anti-VZV activity of the 5'-modified derivatives is further proof of a mechanism of action involving VZV thymidine kinase (TK)-mediated phosphorylation. Similarly, the replacement of the 3'-OH with chlorine showed a decrease of antiviral activity, which can be correlated to the lack of interaction with VZV TK as demonstrated by enzyme assays. These results confirm free 5'-OH and 3'-OH as necessary requirements for efficient recognition by VZV TK and for potent anti-VZV activity in cell culture.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Luoni
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology; D002241:Carbohydrates / Q000737:chemistry*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; D002241:Carbohydrates; D009705:Nucleosides; D013937:Thymidine Kinase