TY - JOUR
T1 - Synthesis and anti-HIV activities of glutamate and peptide conjugates of nucleoside reverse transcriptase inhibitors
AU - Agarwal, Hitesh K.
AU - Chhikara, Bhupender S.
AU - Quiterio, Megrose
AU - Doncel, Gustavo F.
AU - Parang, Keykavous
PY - 2012/3/22
Y1 - 2012/3/22
N2 - 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.
AB - 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.
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U2 - 10.1021/jm201551m
DO - 10.1021/jm201551m
M3 - Article
C2 - 22352809
AN - SCOPUS:84858737126
SN - 0022-2623
VL - 55
SP - 2672
EP - 2687
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -