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

Hitesh K. Agarwal, Kelly Loethan, Deendayal Mandal, Gustavo F. Doncel, Keykavous Parang

Research output: Contribution to journalArticle

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 EC50 = 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.

Original languageEnglish (US)
Pages (from-to)1917-1921
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

Fingerprint

Stavudine
Esters
Derivatives
Satellite Viruses
Chain length
Viruses
HIV
Cytotoxicity
Fluorescein
Alanine
Fatty Acids
Cells
Cell Line
12-aminododecanoic acid
6-carboxyfluorescein

Keywords

  • 2′,3′-Didehydro-2′,3′- dideoxythymidine
  • Anti-HIV
  • Cellular uptake
  • Fatty acids
  • Stavudine

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Synthesis and biological evaluation of fatty acyl ester derivatives of 2′,3′-didehydro-2′,3′-dideoxythymidine. / Agarwal, Hitesh K.; Loethan, Kelly; Mandal, Deendayal; Doncel, Gustavo F.; Parang, Keykavous.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 7, 01.04.2011, p. 1917-1921.

Research output: Contribution to journalArticle

Agarwal, Hitesh K. ; Loethan, Kelly ; Mandal, Deendayal ; Doncel, Gustavo F. ; Parang, Keykavous. / Synthesis and biological evaluation of fatty acyl ester derivatives of 2′,3′-didehydro-2′,3′-dideoxythymidine. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 7. pp. 1917-1921.
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