Synthesis and Antiviral Activity of the Carbocyclic Analogue of the Highly Potent and Selective Anti-VZV Bicyclo Furano Pyrimidines

• Published in: Journal of medicinal chemistry Vol. 50; no. 26; pp. 6485 - 6492
• Main Authors: Migliore, Marco D, Zonta, Nicola, McGuigan, Christopher, Henson, Geoffrey, Andrei, Graciela, Snoeck, Robert, Balzarini, Jan
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27-12-2007
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Line; Cyclopentanes - chemical synthesis; Cyclopentanes - chemistry; Cyclopentanes - pharmacology; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Herpesvirus 3, Human - drug effects; Humans; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Pyrimidine Nucleosides - chemical synthesis; Pyrimidine Nucleosides - chemistry; Pyrimidine Nucleosides - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Stereoisomerism; Structure-Activity Relationship; Varicella zoster virus; Herpesviridae; Alphaherpesvirinae; Selectivity; In vitro; Modeling; Biological activity; Virus; Molecular model; Antiviral; Chemical synthesis; Cyclopentane derivatives; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070357e

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.