Synthesis and broad-spectrum antiviral activity of 7,8-dihydro-7-methyl-8-thioxoguanosine.
2,6,8-Trichloro-7-methylpurine (3) was converted to 2-chloro-8,9-dihydro-7-methyl-8-thioxopurin-6(1H)-one (5) by utilizing the difference in reactivity of the 2-, 6-, and 8-positions in the trichloropurine ring system to nucleophilic displacement. Compound 5 was subsequently glycosylated with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose according to the Vorbrüggen procedure to yield 2-chloro-8,9-dihydro-7-methyl-9-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosy l)-8- thioxopurin-6(1H)-one (6). Removal of the benzoyl protecting groups, followed by amination of 7 with liquid ammonia at 150 degrees C, gave 7,8-dihydro-7-methyl-8-thioxoguanosine (2). The structure of compound 2 was confirmed by X-ray crystallographic analysis. Compounds 1 (7,8-dihydro-7-methyl-8-oxoguanosine) and 2 were evaluated for activity in various animal virus infection models. Against banzi, Semliki Forest, and San Angelo viruses in mice, 2 was highly active when administered before virus inoculation.
Henry
E M
EM
ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.
Kini
G D
GD
Larson
S B
SB
Robins
R K
RK
Alaghamandan
H A
HA
Smee
D F
DF
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D002044:Bunyaviridae Infections / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D005416:Flavivirus; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D012672:Semliki forest virus; D014036:Togaviridae Infections / Q000188:drug therapy; D014961:X-Ray Diffraction
D000998:Antiviral Agents; D006151:Guanosine; C065048:7,8-dihydro-7-methyl-8-thioxoguanosine