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Emtricitabine Prodrugs with Improved Anti-HIV Activity and Cellular Uptake.
MedLine Citation:
PMID:  22917277     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 multi-drug 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.
Authors:
Hitesh K Agarwal; Bhupender S Chhikara; Sitaram Bhavaraju; Dindyal Mandal; Gustavo F Doncel; Keykavous Parang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-23
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  -     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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