Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1.
One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.
Koshida
R
R
Department of Virology, National Bacteriological Laboratory, Stockholm, Sweden.
Cox
S
S
Harmenberg
J
J
Gilljam
G
G
Wahren
B
B
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D017245:Foscarnet; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D017245:Foscarnet; D015215:Zidovudine; D010746:Phosphonoacetic Acid; C002854:alovudine