Emtricitabine prodrugs with improved anti-HIV activity and cellular uptake.
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.
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, United States.
Hitesh K
HK
Agarwal
Bhupender S
BS
Chhikara
Sitaram
S
Bhavaraju
Dindyal
D
Mandal
Gustavo F
GF
Doncel
Keykavous
K
Parang
D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000068679:Emtricitabine; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology*
D019380:Anti-HIV Agents; D011355:Prodrugs; D003841:Deoxycytidine; D000068679:Emtricitabine