2. Academic Validation
  3. Synthesis and biological evaluation of fatty acyl ester derivatives of 2',3'-didehydro-2',3'-dideoxythymidine

Synthesis and biological evaluation of fatty acyl ester derivatives of 2',3'-didehydro-2',3'-dideoxythymidine

  • Bioorg Med Chem Lett. 2011 Apr 1;21(7):1917-21. doi: 10.1016/j.bmcl.2011.02.070.
Hitesh K Agarwal 1,  Kelly Loethan,  Deendayal Mandal,  Gustavo F Doncel,  Keykavous Parang
Affiliations

Affiliation

  • 1 Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
PMID: 21382714 DOI: 10.1016/j.bmcl.2011.02.070
Abstract

A number of 5'-O-fatty acyl derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (stavudine, d4T) were synthesized and evaluated for anti-HIV activities against cell-free and cell-associated virus, cellular cytotoxicity, and cellular uptake studies. The conjugates were found to be more potent than d4T. Among these conjugates, 5'-O-12-azidododecanoyl derivative of d4T (2), displaying EC(50) = 3.1-22.4 μM, showed 4- to 9-fold higher activities than d4T against cell-free and cell-associated virus. Cellular uptake studies were conducted on CCRF-CEM cell line using 5(6)-carboxyfluorescein derivatives of d4T attached through β-alanine (9) or 12-aminododecanoic acid (10) as linkers. The fluorescein-substituted analog of d4T with long chain length (10) showed 12- to 15-fold higher cellular uptake profile than the corresponding analog with short chain length (9). These studies reveal that conjugation of fatty acids to d4T enhances the cellular uptake and anti-HIV activity of stavudine.

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