Synthesis and anti-HIV activities of glutamate and peptide conjugates of nucleoside reverse transcriptase inhibitors

Mono-, di-, and trinucleoside conjugates of glutamate or peptide scaffolds containing nucleoside reverse transcriptase inhibitors were synthesized. Among dinucleoside glutamate ester derivatives, N-myristoylated derivatives showed significantly higher anti-HIV activity than the corresponding N-acetylated conjugates against cell-free virus. Myristoyl-Glu(3TC)-FLT (46, EC ₅₀ = 0.3-0.6 μM) and myristoyl-Glu(FTC)-FLT (47, EC ₅₀ = 0.1-0.4 μM) derivatives were the most active glutamate-dinucleoside conjugates. A trinucleoside glutamate derivative containing AZT, FLT, and 3TC (34, EC ₅₀ = 0.9-1.4 μM) exhibited higher anti-HIV activity than AZT and 3TC against cell-free virus. Compound 34 also exhibited higher anti-HIV activity against multidrug (IC ₅₀ = 5.9 nM) and NNRTI (IC ₅₀ = 12.9 nM) resistant viruses than parent nucleosides. The physical mixture containing FLT-succinate, AZT, 3TC, and glutamic acid exhibited 115-fold less activity against cell associated virus (EC ₅₀ = 91.9 μM) when compared to 34 (EC ₅₀ = 0.8 μM). Other conjugates showed less or comparable potency to that of the corresponding physical mixtures.