Document Detail

Emtricitabine Prodrugs with Improved Anti-HIV Activity and Cellular Uptake.
MedLine Citation:
PMID:  22917277     Owner:  NLM     Status:  Publisher    
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.
Hitesh K Agarwal; Bhupender S Chhikara; Sitaram Bhavaraju; Dindyal Mandal; Gustavo F Doncel; Keykavous Parang
Related Documents :
22299587 - Effect of the non-steroidal anti-inflammatory drugs on the acyl-coa synthetase activity...
1781747 - The distribution of fungiform papillae and taste buds on the human tongue.
23333527 - Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.
22654897 - Fatty acid accumulation and resulting pparα activation in fibroblasts due to trifuncti...
2035477 - Vitamin status of pediatric patients receiving long-term peritoneal dialysis.
17477267 - Microbial population, physicochemical quality, and allergenicity of molluscs and shrimp...
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:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  CO2 Adsorption to Sub-Single Hydration Layer Montmorillonite Clay Studied by Excess Sorption and Neu...
Next Document:  Physical activity is related to timing performance in older adults.