title: Synthesis and antiviral/antitumor activities of certain 3-deazaguanine nucleosides and nucleotides.
abstract: A new procedure for the preparation of the antiviral and antitumor agent 3-deazaguanine (1) and its metabolite 3-deazaguanosine (2) has been developed by reacting methyl 5(4)-(cyanomethyl) imidazole-4(5)-carboxylate (4) and 5-(cyanomethyl)-1- (2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)imidazole-4-carboxylate (6), respectively, with hydrazine. The 3-deazaguanosine 3',5'-cyclic phosphate (13) was prepared from 5-(cyanomethyl)-1-beta-D-ribofuranosyl-imidazole-4-carboxamide 5'-phosphate. Glycosylation of the trimethylsilyl 4 with 1-O-methyl-2-deoxy-3,5-di-O-p-toluoyl-D-ribofuranose in the presence of trimethylsilyl trifluoromethanesulfonate gave the corresponding N-1 and N-3 glycosyl derivatives with alpha-configuration (18 and 20) as the major products, along with minor amounts of the beta-anomers (19 and 21). However, glycosylation of the sodium salt of 4 with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofurano se (17) gave exclusively the beta-anomers (19 and 21) in good yield. Base-catalyzed ring closure of these imidazole nucleosides gave 2'-deoxy-3-deazaguanosine (29), the alpha-anomer 28, and the corresponding N-3 positional isomers 27 and 26. The site of glycosylation and the anomeric configuration of these nucleosides have been assigned on the basis of 1' NMR and UV spectral characteristics and by single-crystal X-ray analysis for 27-29. In a preliminary screening, several of these compounds have demonstrated significant broad-spectrum antiviral activity against certain DNA and RNA viruses in vitro, as well as moderate activity against L1210 and P388 leukemia in cell culture.
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects; D018139:Simplexvirus / Q000187:drug effects; D014616:Vaccinia virus / Q000187:drug effects; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D006151:Guanosine; C010568:3-deazaguanosine; D006147:Guanine; C010567:3-deazaguanine