Synthesis and anti-HIV activities of symmetrical dicarboxylate esters of dinucleoside reverse transcriptase inhibitors

Hitesh K. Agarwal, Karen W. Buckheit, Robert W. Buckheit, Keykavous Parang

Research output: Contribution to journalArticlepeer-review

Abstract

Three nucleoside analogues, 3′-fluoro-2′,3′- dideoxythymidine (FLT), 3′-azido-2′,3′-dideoxythymidine (AZT), and 2′,3′-dideoxy-3′-thiacytidine (3TC) were conjugated with three different dicarboxylic acids to afford the long chain dicarboxylate esters of nucleosides. In general, dinucleoside ester conjugates of FLT and 3TC with long chain dicarboxylic acids exhibited higher anti-HIV activity than their parent nucleosides. Dodecanoate and tetradecanoate dinucleoside ester derivatives of FLT were found to be the most potent compounds with EC 50 values of 0.8-1.0 nM and 3-4 nM against HIV-1US/92/727 and HIV-1IIIB cells, respectively. The anti-HIV activity of the 3TC conjugates containing long chain dicarboxylate diester (EC50 = 3-60 nM) was improved by 1.5-66 fold when compared to 3TC (EC50 = 90-200 nM). This study reveals that the symmetrical ester conjugation of dicarboxylic acids with a number of nucleosides results in conjugates with improved anti-HIV profile.

Original languageEnglish (US)
Pages (from-to)5451-5454
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number17
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

Keywords

  • Anti-HIV
  • Dicarboxylic acid
  • Fatty acid
  • Nucleoside
  • Reverse transcriptase inhibitor

ASJC Scopus subject areas

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

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