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 and its metabolite 3-deazaguanosine was 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, respectively, with hydrazine. The 3-deazaguanosine 3'',5''-cyclic phosphate 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 as the major products, along with minor amounts of the .beta.-anomers. Glycosylation of the sodium salt of 4 with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-.alpha.-D-erythro-pentofuranose gave exclusively the .beta.-anomers in good yield. Base-catalyzed ring closure of these imidazole nucleosides gave 2''-deoxy-3-deazaguanosine (29), the .alpha.-anomer [9-(2-deoxy-.alpha.-D-ribofuranosyl)-3-deazaguanine] 28 and the corresponding N-3 positional isomers. The site of glycosylation and the anomeric configuration of these nucleosides were assigned on the basis of 1H 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 [herpes simplex virus, vaccinia virus, parainfluenza type 3 virus and vesicular stomatitis virus] in vitro, as well as moderate activity against L1210 and P388 leukemia in cell culture.