Synthesis of 1-methyl-5-(3-azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)uracil and 1-methyl-5-(3-azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)uracil. The C-nucleoside isostere of 3'-azido-3'-deoxythymidine and its 2'-"up"-fluoro analogue.
1-Methyl-5-(3-azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)uracil (C-AZT), a C-nucleoside isostere of the potent anti-AIDS nucleoside 3'-azido-3'-deoxythymidine (AZT), was synthesized. 1-Methyl-2'-deoxy-5'-O-tritylpseudouridine (2a) was oxidized with CrO3/pyridine/Ac2O complex to 1-methyl-5-(5-O-trityl-beta-D-glycero-pentofuranos-3-ulosyl) uracil (12a), which was selectively reduced to 1-methyl-5-(5-O-trityl-beta-D-threo-pentofuranosyl)uracil (13a). Mesylation of 13a to 14a followed by nucleophilic displacement of the mesyloxy group with azide afforded 3'-azido-2',3'-dideoxy-5'-O-trityl-1-methylpseudoridine (15a), which was detritylated to C-AZT. In a similar manner, 1-methyl-5-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (C-FMAU, a potent antiherpetic nucleoside) was converted into the 3'-azido analogue (3'-azido-C-FMAU). Both C-AZT and 3'-azido-C-FMAU, however, did not exhibit any significant inhibitory activity against HIV in H9 cells.
Sochacka
E
E
Sloan-Kettering Institute for Cancer Research, Cornell University, New York, New York 10021.
Nawrot
B
B
Pankiewicz
K W
KW
Watanabe
K A
KA
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D006678:HIV / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D007202:Indicators and Reagents; C064770:1-methyl-5-(3-azido-2,3-dideoxy-beta-pentofuranosyl)uracil; C064771:1-methyl-5-(3-azido-2,3-dideoxy-2-fluoro-beta-arabinofuranosyl)uracil; D015215:Zidovudine