Potential anti-AIDS drugs. Lipophilic, adenosine deaminase-activated prodrugs.
Selected acid-stable (2'-fluoro-2',3'-dideoxyarabinofuranosyl)adenine nucleosides containing methyl groups and other lipophilic functions at various positions in the adenine ring were prepared and evaluated as anti-HIV agents. The N6-methyl (1f), N6-benzoyl (1g), and 6-chloro (1i) analogues had modest activity, giving 30-50% protection to ATH8 cells infected with HIV. 2-Methyl (1d), 8-methyl (1h), and 2,N6-dimethyl (1e) substitution, as well as N1-oxide (21) formation, abolished the activity of the parent compound (1a). Several of these compounds, originally designed as agents for treating HIV in the central nervous system, were further investigated as substrates for adenosine deaminase (ADA). Kinetic experiments showed that ADA catalyzed the formation of the anti-HIV active inosine compound 1b from the N6-methyl analogue 1f in a quantitative manner. The anti-HIV activity of 1f and 1i was abolished when the ADA inhibitor, 2'-deoxycoformycin, was added to the test mixture. In contrast, the activity of 1f was significantly enhanced when ADA was added to the test system. These data indicate that 1f and 1i are prodrug forms of 1b in systems containing ADA.
Barchi
J J
JJ
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Marquez
V E
VE
Driscoll
J S
JS
Ford
H
H
Mitsuya
H
H
Shirasaka
T
T
Aoki
S
S
Kelley
J A
JA
D000243:Adenosine Deaminase / Q000378:metabolism*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D007700:Kinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D011355:Prodrugs; D000243:Adenosine Deaminase