title: Synthesis and anti-HIV activities of glutamate and peptide conjugates of nucleoside reverse transcriptase inhibitors.
abstract: 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.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 41 Lower College Road, Kingston, Rhode Island 02881, United States.
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Agarwal
authors.forename: Bhupender S
authors.initials: BS
authors.lastname: Chhikara
authors.forename: Megrose
authors.initials: M
authors.lastname: Quiterio
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Doncel
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D024921:Drug Resistance, Multiple, Viral; D004952:Esters; D005971:Glutamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D009227:Myristic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D019380:Anti-HIV Agents; D004952:Esters; D005971:Glutamates; D009227:Myristic Acids; D009705:Nucleosides; D009842:Oligopeptides; D018894:Reverse Transcriptase Inhibitors