Synthesis and biological evaluation of 5′-O-dicarboxylic fatty acyl monoester derivatives of anti-HIV nucleoside reverse transcriptase inhibitors

Bhanu Pemmaraju, Hitesh K. Agarwal, Donghoon Oh, Karen W. Buckheit, Robert W. Buckheit, Rakesh Tiwari, Keykavous Parang

Research output: Contribution to journalArticle

Abstract

A number of 5′-O-dicarboxylic fatty acyl monoester derivatives of 3′-azido-3′-deoxythymidine (zidovudine, AZT), 2′,3′- didehydro-2′,3′-dideoxythymidine (stavudine, d4T), and 3′-fluoro-3′-deoxythymidine (alovudine, FLT) were synthesized to improve the lipophilicity and potentially the cellular delivery of parent polar 2′,3′-dideoxynucleoside (ddN) analogs. The compounds were evaluated for their anti-HIV activity. Three different fatty acids with varying chain length of suberic acid (octanedioic acid), sebacic acid (decanedioic acid), and dodecanedioic acid were used for the conjugation with the nucleosides. The compounds were evaluated for anti-HIV activity and cytotoxicity. All dicarboxylic ester conjugates of nucleosides exhibited significantly higher anti-HIV activity than that of the corresponding parent nucleoside analogs. Among all the tested conjugates, 5′-O-suberate derivative of AZT (EC 50 = 0.10 nM) was found to be the most potent compound and showed 80-fold higher anti-HIV activity than AZT without any significant toxicity (TC50 >500 nM).

Original languageEnglish (US)
Pages (from-to)1983-1986
Number of pages4
JournalTetrahedron Letters
Volume55
Issue number12
DOIs
StatePublished - Mar 19 2014
Externally publishedYes

Keywords

  • Anti-HIV agents
  • Fatty acids
  • Lipophilicity
  • Nucleosides
  • Reverse transcriptase

ASJC Scopus subject areas

  • Drug Discovery
  • Biochemistry
  • Organic Chemistry

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