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. Epub 2011 Feb 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Cell-Free System
  • Esters / chemistry*
  • Humans
  • Microscopy, Fluorescence
  • Stavudine / chemical synthesis*
  • Stavudine / chemistry
  • Stavudine / pharmacology*


  • Anti-HIV Agents
  • Esters
  • Stavudine