Synthesis of hypoxanthine, guanine, and 6-thiopurine nucleosides of 6-deoxy-D-allofuranose.
Hypoxanthine, guanine, and 6-thiopurine nucleosides of 6-deoxy-D-allofuranose have been prepared as potential antitumor agents. Thus, reaction of 6-deoxy-beta-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-beta-D-allofuranosyl)hypoxanthine (6), 7-(6'-deoxy-beta-D-allofuranosyl)hypoxanthine (7), 9-(6'-deoxy-beta-D-allofuranosyl)guanine (8), and 7-(6'-deoxy-beta-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-beta-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.
D000818:Animals; D003849:Deoxyguanosine / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006147:Guanine; D019271:Hypoxanthine; D007042:Hypoxanthines; D007202:Indicators and Reagents; D007288:Inosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis*; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000494:pharmacology
D007042:Hypoxanthines; D007202:Indicators and Reagents; D009705:Nucleosides; D011684:Purine Nucleosides; D013872:Thionucleosides; C038581:9-(6'-deoxy-beta-D-allofuranosyl)-6-thiopurine; D019271:Hypoxanthine; D007288:Inosine; D006147:Guanine; C038578:7-(6-deoxy-beta-D-allofuranosyl)hypoxanthine; C038577:9-(6'-deoxy-beta-D-allofuranosyl)hypoxanthine; C038580:7-(6'-deoxy-beta-D-allofuranosyl)guanine; C038579:9-(6'-deoxy-beta-D-allofuranosyl)guanine; D003849:Deoxyguanosine