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