Synthesis and antiviral activity of monofluorinated cyclopropanoid nucleosides.
Diastereopure monofluorinated cyclopropanoid nucleosides were synthesized for biological studies. As key intermediates cis- and trans-(+/-)-[1-fluoro-2-(acetoxymethyl)cyclopropyl]methanol were prepared starting from diastereopure fluorinated cyclopropanecarboxylates. The latter were synthesized by copper(i)-catalyzed cyclopropanation of [small alpha]-fluorostyrene with ethyl diazoacetate. After reduction and O-acetylation the diastereomeric (2-fluoro-2-phenylcyclopropyl)methyl acetates were obtained. Oxidative degradation using RuO(4) and reduction of the formed carboxyl group with borane gave the fluorinated alcohols, which were coupled with different nucleobases. After deprotection, the corresponding cyclopropanoid nucleosides of adenine, cytosine, guanine, thymine and uracil were obtained. Antiviral tests revealed for the cis-configured guanosine a low, but specific activity against HSV-1 and HSV-2. In addition low affinities of the adenine derivatives to adenosine receptors were detected.
Rosen
Thomas C
TC
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstr. 40, D-48149 Münster, Germany.
De Clercq
Erik
E
Balzarini
Jan
J
Haufe
Günter
G
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004267:DNA Viruses / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012328:RNA Viruses / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D013237:Stereoisomerism
D000998:Antiviral Agents; D003521:Cyclopropanes; D006845:Hydrocarbons, Fluorinated; D009705:Nucleosides; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2