Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV.
2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo isomer of ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37 degrees C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.
Marquez
V E
VE
Laboratory of Medicinal Chemistry, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Tseng
C K
CK
Mitsuya
H
H
Aoki
S
S
Kelley
J A
JA
Ford
H
H
Roth
J S
JS
Broder
S
S
Johns
D G
DG
Driscoll
J S
JS
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004355:Drug Stability; D015683:Gene Products, gag / Q000032:analysis; D006678:HIV / Q000187:drug effects*; D016655:HIV Core Protein p24; D008213:Lymphocyte Activation / Q000187:drug effects; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology; D014758:Viral Core Proteins / Q000032:analysis
D000998:Antiviral Agents; D015683:Gene Products, gag; D016655:HIV Core Protein p24; D011684:Purine Nucleosides; D014758:Viral Core Proteins