Chemistry and anti-HIV properties of 2'-fluoro-2',3'-dideoxyarabinofuranosylpyrimidines.
The synthesis, chemistry, biochemistry, and anti-HIV activity of a series of 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)pyrimidines have been studied in an attempt to find useful anti-AIDS drugs. Synthesis is carried out via a 2,3-dideoxyribose intermediate which facilitates the preparation of analogues by removing the sugar 3'-hydroxyl group prior to, rather than after, condensation with a uracil or cytosine aglycon. The 2'-F-dd-uridine analogues 7a-d (with H, F, Cl, and CH3 substitution in the 5-position) as well as the 4-deoxy compound (12b) are nonprotective to ATH8 or CEM cells infected with HIV-1. In the corresponding cytidine series, the 5-chloro analogue (11) is inactive. However, 2'-fluoro-2',3'-dideoxyarabinosylcytosine, 10a, and its 5-fluoro analogue, 10b, are both active. While neither compounds is a potent as ddC or 5-F-ddC (2b), 10b gives complete protection against the cytopathic effects of HIV in both host cell lines. 2'-Fluoro substitution confers increased chemical and enzymatic stability on dideoxynucleosides. Even though dideoxy pyrimidine nucleosides are inherently more stable than the corresponding purine analogues toward acid-catalyzed cleavage of the glycosidic bond, 2'-fluoro substitution (10a) still increases stabilization relative to ddC (2b). No detectable deamination by partially purified cytidine deaminase is observed with the 2'-fluoro compounds 10a, 10b, or 11 under conditions which rapidly deaminate cytidine. A small amount of 2'-F-dd-ara-U (7a) is formed from 10a in monkey plasma after greater than 24 h of exposure. The octanol-water partition coefficients for the dideoxynucleosides in this study indicate their hydrophilic character, with log P values varying from -0.28 to -1.18.
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
M A
MA
Siddiqui
J S
JS
Driscoll
V E
VE
Marquez
J S
JS
Roth
T
T
Shirasaka
H
H
Mitsuya
J J
JJ
Barchi
J A
JA
Kelley
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000378:metabolism; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D008253:Macaca mulatta / Q000097:blood; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D003561:Cytarabine; C065050:1-(2,3-dideoxy-2-fluoropentofuranosyl)cytosine; C075252:1-(2,3-dideoxy-2-fluoropentofuranosyl)-5-fluorocytosine; D016047:Zalcitabine; D003564:Cytidine Deaminase