Synthesis and biological evaluation of endocyclic 2',3'-didehydro-2',3'-dideoxymethanocarba adenosine.
This is the first report describing the synthesis and conformation of methanocarba nucleosides incorporating an endo (beta-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.
Quirk Dorr
Danaè R
DR
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 308 Harvard Street S. E., Minneapolis, MN 55455, USA.
Vince
Robert
R
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014709:Vero Cells
D058892:Adenosine Deaminase Inhibitors; D000998:Antiviral Agents; D009705:Nucleosides; D011994:Recombinant Proteins; D016048:Dideoxyadenosine; D054303:HIV Reverse Transcriptase