Synthesis and biological activity of 5-thiobredinin and certain related 5-substituted imidazole-4-carboxamide ribonucleosides.
A number of 5-substituted imidazole-4-carboxamide ribonucleosides were prepared and tested for their biological activity. Treatment of 5-chloro-1-beta-D-ribofuranosylimidazole-4-carboxamide (2) with methanethiol provided 5-(methylthio)-1-beta-D-ribofuranosylimidazole-4-carboxamide (3a). Similar treatment of 2 with ethanethiol or benzenemethanethiol gave the corresponding 5-ethylthio and 5-benzylthio derivatives 3b and 3c. Oxidation of 3a and 3b with m-chloroperoxybenzoic acid furnished the corresponding sulfonyl derivatives 4a and 4b. Reductive cleavage of 3c with sodium naphthalene or Na/NH3 gave 5-mercapto-1-beta-D-ribofuranosylimidazole-4-carboxamide (5-thiobredinin, 5). Direct treatment of 2 with sodium hydrosulfide provided an alternate route to 5, the structure of which was established by single-crystal X-ray analysis. 5-Thiobredinin has a zwitterionic structure similar to that of bredinin. Glycosylation of persilylated ethyl 5(4)-methylimidazole-4(5)-carboxylate (6) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of SnCl4 provided a quantitative yield of the corresponding tri-O-benzoyl nucleoside 7. Debenzoylation of 7 with MeOH/NH3 at ambient temperature gave ethyl 5-methyl-1-beta-D-ribofuranosylimidazole-4-carboxylate (8). Further ammonolysis of 8 or 7 at elevated temperature and pressure gave 5-methyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (9). All of these ribonucleosides were tested in Vero cell cultures and in mice against certain viruses. Compounds 3a and 3c exhibited significant activity against vaccinia virus in vitro, whereas 4a was effective against Rift Valley fever virus in mice. 5-Thiobredinin failed to exhibit appreciable antiviral or cytostatic activity (against L1210 and P388) in cell culture.
Wood
S G
SG
Upadhya
K G
KG
Dalley
N K
NK
McKernan
P A
PA
Canonico
P G
PG
Robins
R K
RK
Revankar
G R
GR
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D007093:Imidazoles / Q000627:therapeutic use*; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects; D012254:Ribavirin / Q000494:pharmacology; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D012296:Rift Valley fever virus / Q000187:drug effects; D018139:Simplexvirus / Q000187:drug effects; D014035:Togaviridae / Q000187:drug effects; D014616:Vaccinia virus / Q000187:drug effects; D014780:Viruses / Q000187:drug effects*; D014961:X-Ray Diffraction
D007093:Imidazoles; D012263:Ribonucleosides; C032566:imidazole-4-carboxamide; D000620:Aminoimidazole Carboxamide; D012254:Ribavirin; C046477:5-thiobredinin