Synthesis and biological activity of some imidazo[4,5-b]pyrazines and their ribonucleosides as purine analogs

Abstract

The 1 -j3-D-ribofuranosyl derivative 9 of lf/-imidazo[4,5-6jpyrazine (5), a structural analog of the antibiotic nebularine (9-0-D -ribofuranosylpurine), has been prepared by acid-catalyzed fusion of 5 with 1,2,3,5-tetra-0-acetyl-j3-D-ribofuranose and subsequent removal of the acetyl groups. Oxidation of 5 with peracetic acid furnished l/f-imidazo[ 4,5-6 jpyrazine 4(7)-oxide (6). Oxidation of the triacetyl derivative of 9 with m-chloroperoxybenzoic acid, followed by the removal of the protecting groups, provided the inosine analog l-(0-D-ribofuranosyl)imidazo[4,5-6 jpyrazine 4-oxide (11). The site of attachment of the ribosyl moiety in 9 and 11 was substantiated by comparison of their uv spectra with those of the model 1-methylimidazo[4,5-6 jpyrazine (13) and its 4-oxide 15, synthesized by unequivocal routes. The structure of 11 was also confirmed by X-ray crystallography. In the crystal, the nucleoside exists in the anti conformation, the oxygen of the W-oxide function participating in hydrogen bonding with the 2'-hydroxyl group of a neighboring molecule. Compounds 6 and 11 inhibited the in vitro growth of Escherichia coli K12 by 50% at 1 X 10'5 and 6 X 10_6M, respectively. The nebularine analog 9 was inactive. The inhibition of growth was reversed competitively by the natural purines. None of the analogs interfered with the in vitro growth of leukemia L-1210, mammary carcinoma TA-3, and Burkitt's lymphoma cells. In a cell free extract from E. coli, the ribofuranosyl derivative 11 underwent cleavage of its glycosidic bond to furnish the base 6. Imidazopyrazine 4(7)-oxide (6) interfered with the activity of xanthine oxidase from milk, whereas the nucleoside 11 was ineffective.

Synthesis and the crystal structure of 4-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-6-methyl-1,2,4-triazin-3-(4H)-one 1-oxide, a structural analog of thymidine

“…A similar treatment of 3, however, produced only intractable mixtures. A careful monitoring of this reaction revealed that, initially, the reaction mixture to convert sodium methylmercaptide to a disulfide, and, under these conditions, compound 4 was obtained in fairly good yield (50%). Oxidation of 4 was first attempted by treatment with m-chloroperoxybenzoic acid in refluxing benzene, the method that Szekeres et al6 used for the preparation of 3-methoxy-l,2,4triazine 1-oxide.…”