Synthesis and antiviral activity of cyclopropyl-spirocarbocyclic adenosine, (4R,5S,6R,7R)-4-(6-amino-9H-purin-9-yl)-7-(hydroxymethyl)spiro[2.4]heptane-5,6-diol against hepatitis C virus

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 13; pp. 3982 - 3985
• Main Authors: Gadthula, Srinivas, Rawal, Ravindra K, Sharon, Ashoke, Wu, Dong, Korba, Brent, Chu, Chung K
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.07.2011; Elsevier
• Subjects: adenosine; Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; antiviral properties; Biological and medical sciences; Cells, Cultured; chemistry; Crystallography, X-Ray; genotype; Hepacivirus - drug effects; Hepatitis C virus; Heptanes - chemical synthesis; Heptanes - chemistry; Heptanes - pharmacology; Humans; Inhibitory Concentration 50; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Adenine derivatives; Purine derivatives; Cyclopropane derivatives; Enzyme; Transferases; Carbanucleoside; In vitro; Biological activity; RNA-directed RNA polymerase; Spiran; Virus; Nucleotidyltransferases; NS5B; Antiviral; Nucleoside; Anti-HCV; Flaviviridae; Chemical synthesis; Hepatitis C virus; Carbocyclic nucleoside; Hepacivirus; X-ray structure; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.05.012

An efficient method was developed for the synthesis of 6-exocyclic methylene carbocyclic intermediate 4. The Simmons–Smith cyclopropanation protocol was applied on the 6-exocyclic methylene of intermediate 4 and demonstrated its utility for the synthesis of novel class of a spiro-carbocyclic nucleoside analog 8. The titled compound 8 demonstrated a significant antiviral activity against HCV with EC₅₀ values of 0.273 and 0.368μM in genotypes 1A and 1B, respectively.