Synthesis of Hypoxanthine, Guanine, and 6-Thiopurine Nucleosides of 6-Deoxy-D-allofuranose

Document Type

Article

Publication Date

1-1-1983

Abstract

Hypoxanthine, guanine, and 6-thiopurine nucleosides of 6-deoxy-D-allofuranose have been prepared as potential antitumor agents. Thus, reaction of 6-deoxy-|8-D-allofuranosyl bromide (1) with the trimethylsilyl derivatives of hypoxanthine and guanine afforded mixtures of the 9- and the 7-substituted bases, which were separated and deblocked with ammonia to give 9-(6′-deoxy-|9-D-allofuranosyl)hypoxanthine (6), 7-(6′-deoxy-β-D-allofuranosyl)hypoxanthine (7), 9-(6′-deoxy-/3-D-allofuranosyl)guanine (8), and 7-(6′-deoxy-/3-D-allofuranosyl)guanine (9). The two nucleosides with the purine joined at the N-9 position, namely, 6 and 8, are easily distinguished from the other two nucleosides (7 and 9), having N-7 junctions, by their NMR spectra. Reaction of 1 with the trimethylsilyl derivative of 6-chloropurine afforded 10, which upon treatment with thiourea and deblocking gave 9-(6′-deoxy-/3-D-allofuranosyl)-6-thiopurine (12). The hypoxanthine and guanine nucleosides showed no inhibition of mouse leukemia L1210 when tested in vivo, but the thiopurine nucleoside 12 showed strong inhibition of growth of L1210 both in vivo and in vitro. Compound 7 strongly inhibited purine nucleoside phosphorylase (KI = 8.8 X 10-5 M), while compounds 8, 9, 6, and 12 were inactive. © 1983, American Chemical Society. All rights reserved.

Publication Title

Journal of Medicinal Chemistry

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