ABSTRACT:
We recently identified D-D4FC as a highly selective inhibitor of HIV-1 and HIV-2 with a unique cross-resistance profile. However, certain d4N are unstable under acidic conditions. We reasoned that introducing a vinylic fluoride moiety into the D- and L- nucleosides should eliminate this potential problem. The strategy for the synthesis of more than 30 analogues was based on direct coupling of the sugar moiety with a variety of heterocycles to obtain our target compounds. The 2-fluoro-2,3-unsaturated sugar moiety was prepared from 1,2-O-isopropylidene-glyceraldehyde via a (R)- or (S)-2-fluoro-butenolide intermediate. The key intermediate was condensed with a variety of heterocycles to give the desired compounds. These were evaluated for antiviral activity against HIV-1 and M184V cloned viruses in human PBMC. For the L- series, cytosine, 5-fluoro-cytosine, and adenine derivatives demonstrated significant activity against HIV-1 (EC50 0.51, 0.17 and 1.5 µM, respectively) with no apparent cytotoxicity at 100 µM in human PBMC, Vero and CEM cells. For the D-series, the adenine, inosine, 6-chloro-2-aminopurine, guanine, 2,6-diaminopurine and 5-fluorocystine derivatives had selective antiviral activity (EC50 0.04, 0.5, 0.09, 1.5, 1.1, and 0.4 respectively). Interestingly, whereas the L-nucleosides were essentially inactive against the 184V variant, the D-enantiomers retained their potency. Of significance, some of these compounds also demonstrated anti-HBV activity. In view of the potent and selective activity against the M184V HIV-1 variants, lack of cross-resistance with other known antiviral agains, dual antiviral activity against HIV-1 and HBV, and increased chemical stability, advanced biochemical and pharmacological studies with this rich class of active D-2'-F-d4N are warranted.
