Direct C-glycosylation of guanine analogs: the synthesis and antiviral activity of certain 7- and 9-deazaguanine C-nucleosides

• Published in: Journal of medicinal chemistry Vol. 33; no. 10; pp. 2750 - 2755
• Main Authors: Girgis, Nabih S, Michael, Maged A, Smee, Donald F, Alaghamandan, Hassan A, Robins, Roland K, Cottam, Howard B
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.10.1990
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - therapeutic use; Carbohydrates. Nucleosides and nucleotides; Chemical Phenomena; Chemistry; Chemistry, Physical; Exact sciences and technology; Glycosylation; Guanosine - analogs & derivatives; Guanosine - chemistry; Mice; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Semliki forest virus; Togaviridae Infections - drug therapy; Semliki forest virus; C-Nucleoside; Nitrogen heterocycle; Rodentia; Lactam; Togaviridae; Guanidines; Deazanucleoside; Biological activity; Virus; In vivo; Vertebrata; Mammalia; Mouse; Animal; Bicyclic compound; Alphavirus; Antiviral; Ribonucleoside
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00172a011

C-Glycosylation of two guanine analogues, 9-deaza- and 7-deazaguanine, has been achieved under Friedel-Crafts conditions, providing a direct synthetic route to 9-deazaguanosine (4; 2-amino-7-beta-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one) and 8-beta-D-ribofuranosyl-7-deazaguanine (16), respectively. This electrophilic C-glycosylation was applied successfully to six guanine and substituted-guanine analogues resulting in yields of approximately 50%. This represents the first reported C-ribosylation of preformed nitrogen heterocycles isosteric with guanine. These C-nucleosides were evaluated for their ability to provide protection against a lethal Semliki Forest virus infection in mice, relative to 7-thia-8-oxoguanosine which was used as a positive control. Two of the C-nucleosides, 2-amino-6-chloro-5-methyl-7-beta-D-ribofuranosyl-5H-pyrrolo [3,2-d]pyrimidin-4(3H)-one (12) and the corresponding 6-bromo derivative (13), showed good prophylactic activity in this virus model system.