Emtricitabine prodrugs with improved anti-hiv activity and cellular uptake

Hitesh K. Agarwal, Bhupender S. Chhikara, Sitaram Bhavaraju, Dindyal Mandal, Gustavo F. Doncel, Keykavous Parang

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)467-476
Number of pages10
JournalMolecular Pharmaceutics
Volume10
Issue number2
DOIs
StatePublished - Feb 4 2013
Externally publishedYes

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

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