SYNTHESIS AND BIOLOGICAL EVALUATION OF ENDOCYCLIC 2′,3′-DIDEHYDRO- 2′,3′-DIDEOXYMETHANOCARBA ADENOSINE

• Published in: Nucleosides, nucleotides & nucleic acids nucleotides & nucleic acids, 2002-12, Vol.21 (10), p.665-680
• Main Authors: Dorr, Danaè R. Quirk, Vince, Robert
• Format: Article
• Language: English
• Subjects: Adenosine Deaminase Inhibitors; Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Cattle; Cells, Cultured; Cercopithecus aethiops; Crystallography, X-Ray; Dideoxyadenosine - analogs & derivatives; Dideoxyadenosine - chemical synthesis; Dideoxyadenosine - pharmacology; Herpesvirus 1, Human - drug effects; HIV Reverse Transcriptase - antagonists & inhibitors; HIV-1 - drug effects; Humans; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Nucleosides - chemical synthesis; Nucleosides - pharmacology; Recombinant Proteins - antagonists & inhibitors; Vero Cells
• ISSN: 1525-7770; 1532-2335
• DOI: 10.1081/NCN-120015724

This is the first report describing the synthesis and conformation of methanocarba nucleosides incorporating an endo ( β -face) cyclopropyl at the 2′,3′ position of 2′,3′-didehydro-2′,3′-dideoxy carbocyclic nucleosides. These nucleoside isosteres have been shown to exist in a unique extreme eastern conformation. This prediction was confirmed by x-ray crystallography and high resolution NMR spectroscopy. As expected, the methanocarba adenosine compound was neither a substrate nor an inhibitor of adenosine deaminase. However, some of the compounds synthesized demonstrated moderate antiviral activity against HSV-1. The methanocarba adenosine and its triphosphate form were evaluated as inhibitors of HIV-1 reverse transcriptase.