Synthesis and antitumor activity of 7- and 9-(6'-deoxy-alpha-L-talofuranosyl) hypoxanthine and 9-(6'-deoxy-alpha-L-talofuranosyl)-6-thiopurine.
Reaction of 6-deoxy-2,3,5-tris-O-(p-nitrobenzoyl)-L-talofuranosyl bromide (1) with the trimethylsilyl derivative of hypoxanthine, followed by removal of blocking groups, afforded 9- (6) and 7-(6'-deoxy-alpha-L-talofuranosyl)hypoxanthine (7). A study of the published optical rotations and circular dichroic (CD) spectra of pentofuranosylpurines and of (6'-deoxy-beta-D-allo- and -alpha-L-talofuranosyl)purines prepared here suggests that the sign of rotation and the sign of the longer wavelength Cotton effect is determined solely by the configuration of C-1' and its position of attachment to the purine ring. For C-1' R nucleosides, the sign is negative for N-9-linked purine nucleosides and positive for the N-7-linked isomers, and vice versa for C-1'S purine nucleosides. Reaction of 1 with the trimethylsilyl derivative of 6-chloropurine afforded 4, which upon treatment with thiourea and deblocking yielded 9-(6'-deoxy-alpha-L-talofuranosyl)-6-thiopurine (8). Unlike the previously prepared 7-(6'-deoxy-beta-D-allofuranosyl) hypoxanthine which strongly inhibited purine nucleoside phosphorylase, compounds 6-8 did not inhibit this enzyme. Compound 8 significantly inhibited the growth of L1210 tumor cells in vitro and in vivo.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004353:Drug Evaluation, Preclinical; 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; D015122:Mercaptopurine / Q000627:therapeutic use; D051379:Mice; D009904:Optical Rotation; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000627:therapeutic use; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D011684:Purine Nucleosides; D013872:Thionucleosides; D007288:Inosine; C039371:7-(6'-deoxytalofuranosyl)hypoxanthine; C039370:9-(6'-deoxytalofuranosyl)hypoxanthine; C039372:9-(6'-deoxytalofuranoysl)-6-thiopurine; D015122:Mercaptopurine