Synthesis of 2′,3′-dideoxynucleoside 5′-α-P-borano-β,γ-(difluoromethylene)triphosphates and their inhibition of HIV-1 reverse transcriptase

The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can entirely bypass cellular phosphorylation. AZT 5'(alpha-R-P-borano-beta,gamma-(difluoromethylene)triphosphate (5'-(alpha B-beta gamma CF2TP) has been identified as a potent inhibitor of HIV- 1 reverse transcriptase (HIV- I RT). This work was aimed at confirming that 5'-alpha B-beta gamma CF2TP is a useful generic triphosphate moiety and can render antiviral ddNs with potent inhibitory effects on HIV-1 RT. Thus, 10 ddNs were converted to their 5'-(alpha beta gamma CF2-TPs via a sequence (one-pot) of reactions: formation of an activated phosphite, formation of a cyclic triphosphate, boronation, and hydrolysis. Other synthetic routes were also explored. All ddN 5'-alpha B-beta gamma CF(2)TPs tested exhibited essentially the same level of inhibition of HIV-1 RT as the corresponding ddNTPs. A conclusion can be made that 5'-alpha B-beta gamma CF2TP is a generic and promising triphosphate mimic (P3M) concerning HIV-1 RT inhibition and serum stability. It is anticipated that use of 5'-alpha B-beta gamma CF2TP as P3M moiety will lead to the discovery of a new class of anti-HIV agents.