Synthesis and antiviral activity of the carbocyclic analogue of the highly potent and selective anti-VZV bicyclo furano pyrimidines.
Carbocyclic nucleoside analogues are catabolically stable since they are resistant to phosphorolytic cleavage by pyrimidine nucleoside phosphorylase enzymes. The carbocyclic analogue (C-BCNA) of the highly potent and selective anti-VZV bicyclic nucleoside analogue (BCNA) 6-pentylphenylfuro[2,3-d]pyrimidine-2'-deoxyribose was synthesized using carbocyclic 2'-deoxyuridine as starting material. C-BCNA was found to be chemically more stable than the furano lead, but it was shown to be significantly less antivirally active than its parent nucleoside analogue. It was noted to have a 10-fold lower inhibitory activity against the VZV-encoded thymidine kinase. This reduction of activity may be attributed to the different conformation of the sugar and base, as predicted by computational studies and supported by NMR studies. However, other factors besides affinity for VZV-TK must account for the greatly reduced antiviral potency.
Welsh School of Pharmacy, Cardiff University, UK.
Marco D
MD
Migliore
Nicola
N
Zonta
Christopher
C
McGuigan
Geoffrey
G
Henson
Graciela
G
Andrei
Robert
R
Snoeck
Jan
J
Balzarini
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C527718:3-(3-hydroxy-4-(hydroxymethyl)cyclopentyl)-6-(4-pentylphenyl)furo(2,3-d)pyrimidin-2(3H)-one; D000998:Antiviral Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003517:Cyclopentanes; D005663:Furans; D011741:Pyrimidine Nucleosides; D011743:Pyrimidines