title: Synthesis of beta-enantiomers of N4-hydroxy-3'-deoxypyrimidine nucleosides and their evaluation against bovine viral diarrhoea virus and hepatitis C virus in cell culture.
abstract: N4-Hydroxycytidine (NHC) was recently reported to have anti-pestivirus and anti-hepacivirus activity. It is thought that this nucleoside acts as a weak alternative substrate for the hepatitis C virus (HCV) polymerase. In addition to NHC, 3'-deoxyuridine (3'-dU) was found to inhibit bovine diarrhoea virus (BVDV) production by 1 log10 at 37.2 microM. These initial findings prompted the synthesis of beta-D and beta-L analogues of (i) base-modified 3'-deoxy-NHC; (ii) 3'-deoxyuridine; and 3'-deoxycytidine. The antiviral activity of these 42 nucleosides was evaluated against BVDV and HCV bicistronic replicon in cell culture. Among the NHC analogues, the antiviral activity observed for the beta-L-3'-deoxy-5-fluoro-derivative 1-(3-deoxy-beta-L-erythro-pentofuranosyl)-5-fluoro-4-hydroxyaminopyrimidin-2(1H)-one and the beta-D-3'-deoxy-5-iodo-derivative 1-(3-deoxy-beta-D-erythro-pentofuranosyl)-5-iodocytosine in the replicon system (1 log10 reduction at 100 microM) was due to the concomitant toxicity towards intracellular ribosomal RNA levels (CC90 equal or lower than the EC90). In conclusion, none of the newly synthesized derivatives exhibited enhanced antiviral activity compared to the parent nucleoside NHC.
authors.affiliation: Pharmasset Inc., Tucker, Ga., USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Hollecker
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
authors.forename: Chung K
authors.initials: CK
authors.lastname: Chu
authors.forename: Stefania
authors.initials: S
authors.lastname: Lostia
authors.forename: Tamara R
authors.initials: TR
authors.lastname: McBrayer
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Stuyver
authors.forename: J Christian
authors.initials: JC
authors.lastname: Mason
authors.forename: Jinfa
authors.initials: J
authors.lastname: Du
authors.forename: Suguna
authors.initials: S
authors.lastname: Rachakonda
authors.forename: Junxing
authors.initials: J
authors.lastname: Shi
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Kyochi A
authors.initials: KA
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects*; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides