Abstract
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, EC50 = 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 (EC50 = 0.7-88.6 μM) and the corresponding physical mixtures of FTC and myristic acid (14, EC50 = 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 (IC90 = 15.7-16.1 nM) showed 6.6- and 35.2 times higher activity than FTC (IC90 = 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.
Original language | English (US) |
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Pages (from-to) | 467-476 |
Number of pages | 10 |
Journal | Molecular Pharmaceutics |
Volume | 10 |
Issue number | 2 |
DOIs | |
State | Published - Feb 4 2013 |
Externally published | Yes |
Keywords
- (-)-2′,3′-dideoxy-5-fluoro-3′-thiacytidine
- anti-HIV
- cellular uptake
- cytotoxicity
- fatty acids
ASJC Scopus subject areas
- Pharmaceutical Science
- Molecular Medicine
- Drug Discovery