ChemInform Abstract: Synthesis, in vitro anti‐HIV Activity, and Biological Stability of 5′‐O‐Myristoyl Analogue Derivatives of 3′‐Fluoro‐2′,3′‐dideoxythymidine (FLT) as Potential Bifunctional Prodrugs of FLT.

Parang, Keykavous; Knaus, Edward E.; Wiebe, L. I.

doi:10.1002/chin.199837253

Cited by 4 publications

(10 citation statements)

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“…5′- O -(Fatty acyl) esters of FTC ( 5 – 7 ) were consistently active against both cell-free and cell-associated virus, and exhibited higher anti-HIV activity than FTC (Table ). The FTC esters displayed the highest anti-HIV activity against cell-free virus (EC 50 = 0.04–0.2 μM) among all the previously reported fatty acyl ester derivatives and their parent NRTIs. ,− …”

Section: Resultsmentioning

confidence: 88%

“…The polar nature of FTC (calculated Log P for FTC = −1.29) limits its efficient cellular uptake. We have previously reported the synthesis and evaluation of fatty acyl ester prodrugs of 3TC, AZT, d4T, and FLT. ,− These studies showed improvement in the anti-HIV activities of nucleoside analogues after conjugation with myristic acid analogues. ,,− In addition, myristic acid analogues have moderate activity against N -myristoyltransferase (NMT), a crucial enzyme involved in the life cycle of HIV (e.g., capsid protein p17, Pr160 gag‑pol , Pr55 gag , p27 nef ). , NMT catalyzes the myristoylation of viral proteins at N -terminal glycine and makes them more hydrophobic to improve their protein–protein and protein–membrane interactions . Several myristic acid analogues inhibit NMT, − thereby reducing replication of HIV-1.…”

Section: Introductionmentioning

confidence: 99%

“…Several myristic acid analogues inhibit NMT, − thereby reducing replication of HIV-1. Our previous studies indicate that the conjugation of three fatty acids, myristic acid, 12-azidododecanoic acid, and 12-thioethyldodecanoic acid, with NRTIs generates more potent analogues. ,− …”

Section: Introductionmentioning

confidence: 99%

“…Herein, we discuss the synthesis and anti-HIV activity of fatty acyl esters of FTC as nucleoside prodrugs. The selection of the fatty acids, myristic acid, 12-azidododecanoic acid, and 12-thioethyldodecanoic acid, was based on previous results about fatty acyl derivatives of other nucleosides. ,− We hypothesized that the FTC conjugation with the myristic acid analogues would enhance the cellular uptake through improved lipophilicity. The fatty acyl esters are expected to get hydrolyzed intracellularly to produce two anti-HIV active agents, the nucleoside analogue and the fatty acid targeting RT and NMT enzymes, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Emtricitabine Prodrugs with Improved Anti-HIV Activity and Cellular Uptake

et al. 2012

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Three fatty acyl conjugates of (-)-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC, emtricitabine) were synthesized and evaluated against HIV-1 cell-free and cell-associated virus and compared with the corresponding parent nucleoside and physical mixtures of FTC and fatty acids. Among all the compounds, the myristoylated conjugate of FTC (5, EC(50) = 0.07-3.7 μM) displayed the highest potency. Compound 5 exhibited 10-24 and 3-13-times higher anti-HIV activity than FTC alone (EC(50) = 0.7-88.6 μM) and the corresponding physical mixtures of FTC and myristic acid (14, EC(50) = 0.2-20 μM), respectively. Cellular uptake studies confirmed that compound 5 accumulated intracellularly after 1 h of incubation and underwent intracellular hydrolysis in CCRF-CEM cells. Alternative studies were conducted using the carboxyfluorescein conjugated with FTC though β-alanine (12) and 12-aminododecanoic acid (13). Acylation of FTC with a long-chain fatty acid in 13 improved its cellular uptake by 8.5-20 fold in comparison to 12 with a short-chain β-alanine. Compound 5 (IC(90) = 15.7-16.1 nM) showed 6.6- and 35.2 times higher activity than FTC (IC(90) = 103-567 nM) against multidrug resistant viruses B-NNRTI and B-K65R, indicating that FTC conjugation with myristic acid generates a more potent analogue with a better resistance profile than its parent compound.

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Section: Resultsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Emtricitabine Prodrugs with Improved Anti-HIV Activity and Cellular Uptake

et al. 2012

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“…We previously reported the synthesis and evaluation of several 5′- O -fatty acyl esters of AZT, FLT, and 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) for inhibition of HIV-1. − These conjugates were designed to achieve anti-HIV activity through inhibition of reverse transcriptase and NMT by nucleosides and fatty acids.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Fatty Acyl Ester Derivatives of (−)-2′,3′-Dideoxy-3′-thiacytidine

et al. 2012

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A number of fatty acyl derivatives of (-)-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5'-O-fatty acyl derivatives of 3TC (EC(50) = 0.2-2.3 μM) were more potent than the corresponding monosubstituted N(4)-fatty acyl (EC(50) = 0.4-29.4 μM) and 5'-O-N(4)-disubstituted (EC(50) = 72.6 to >154.0 μM) derivatives of the nucleoside. 5'-O-Myristoyl (16) and 5'-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC(50) = 0.2-0.9 μM) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC(50) = 11.4-32.7 μM). The EC(90) values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5'-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus.

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Synthesis and Anti-HIV Activities of Glutamate and Peptide Conjugates of Nucleoside Reverse Transcriptase Inhibitors

et al. 2012

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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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ChemInform Abstract: Synthesis, in vitro anti‐HIV Activity, and Biological Stability of 5′‐O‐Myristoyl Analogue Derivatives of 3′‐Fluoro‐2′,3′‐dideoxythymidine (FLT) as Potential Bifunctional Prodrugs of FLT.

Cited by 4 publications

References 1 publication

Emtricitabine Prodrugs with Improved Anti-HIV Activity and Cellular Uptake

Emtricitabine Prodrugs with Improved Anti-HIV Activity and Cellular Uptake

Synthesis and Biological Evaluation of Fatty Acyl Ester Derivatives of (−)-2′,3′-Dideoxy-3′-thiacytidine

Synthesis and Anti-HIV Activities of Glutamate and Peptide Conjugates of Nucleoside Reverse Transcriptase Inhibitors

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