Amino acid phosphoramidates of antiviral 3-deazaadenosine analogs exhibit high potency and low cytotoxicity

Currently, nucleoside based reverse transcriptaseinhibitors are being successfully employed as potent antiviral agents. Although the mechanism of action is unknown, the 3-deazaadenosine analogs, 3-deazaadenosine (DZA), 3-deaza-(±)-aristeromycin (DZAri), 3-deazaneplanocin A (DZNep) have been found to have significant antiviral activity against AZT sensitive and resistant clinical isolates of HIV-1. Recently, we have demonstrated that amino acid phosphoramidates of AZT and d4T exhibit significant antiviral activity with considerably reduced cytotoxicity. Consequently, in order to examine the generality of this approach, we have constructed phenylalanine and tryptophan phosphoramidates of DZA, DZAri and DZAra-A. Preliminary results have demonstrated that the tryptophan phosphoramidate is nearly 40-fold more active than DZA, while the phenylalanine derivative is nearly 10-fold more active than DZA. As was observed for AZT-phosphoramidates, the DZA phosphoramidates exhibited no detectable cytotoxicity to PBMCs at concentrations as high as 10 μM. Unlike DZA itself, the phosphoramidates of DZA did not exhibit activity against AZT resistant HIV-1. Additionally, both DZA phosphoramidates were also effective against HIV-1 in MT4 cells.