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Among the purine and pyrimidine 2′,3′-dideoxynucleosides, 2′,3′-didehydro-2′,3′-dideoxynucleosides, 3′-azido-2′,3′-dideoxynucleosides and 3′-fluoro-2′,3′-dideoxynucleosides, several congeners have been identified which achieve a potent and selective inhibition of HIV-1 replication in vitro.

A number of oligodeoxynucleotides containing thymine bases linked to the deoxyribose in the α-configuration have been synthesized. In view of the possible activity of α-origomers as antisense compounds against HIV replication, the effects of α-thymidylate oligomers (α-dTn, n=1-1-16) in a poly (A)-directed HIV reverse transcriptase (RT) reaction were investigated. No priming activity could be detected with the α-dT oligomers at concentrations up to 100 μM. However, in the presence of the natural β-dT12-18 primer, 50% inhibition of RT activity was achieved at a concentration of about 1 μM with the α-dT oligomers containing ≥ 10 monomer units. The kinetics of RT inhibition by the α-decamer was found to be competitive with respect to the natural primer, β-dT10.

Several 2′,3′-dideoxynucleosides have proven to be effective against HIV-1 in cell culture. The 2′,3-unsaturated analogues dideoxycytidinene (D4C) and dideoxythymidinene (D4T) are among the most potent and selective inhibitors of HIV-1 replication in vitro. However, 2′,3′-didehydro-2′,3′-dideoxynucleosides are relatively unstable. A chlorine substituent at the 2′-position increases the stability, and, therefore, some 2′-chloro-2′,3′-didehydro-2′,3′-dideoxynucleosides were synthesized and evaluated for anti-HIV-1 activity.

The advent of AIDS has prompted the search for effective anti-HIV-1 agents, and, in view of the efficacy of azidothymidine in the treatment of AIDS, 2′,3′-dideoxynucleosides and analogues thereof have been considered as the most obvious candidates for AIDS chemotherapy. Various substituents have been introduced at the 3′-position, but only the 3′-azido and 3′-fluoro derivatives were found active against HIV-1. Introduction of a fluorine in organic compounds frequently causes a dramatic change in their biological activity. The stability of the carbon-fluorine bond and the strong electronegative character of fluorine, altering the electronic properties of the substituted molecule, led us to synthesize dideoxynucleosides with a fluorine substituent at different positions. The synthe