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Tetrahedron Lett. 2014 Mar 19;55(12):1983-1986.

Synthesis and Biological Evaluation of 5'-O-Dicarboxylic Fatty Acyl Monoester Derivatives of Anti-HIV Nucleoside Reverse Transcriptase Inhibitors.

Author information

  • 1Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, United States.
  • 2ImQuest BioSciences Inc. 7340 Executive Way, Suite R, Frederick, MD, 21704, United States.
  • 3Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, United States ; School of Pharmacy, Chapman University, Orange, CA, 92618, United States.

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) analogues. 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 (EC50 = 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).

KEYWORDS:

Anti-HIV agents; Fatty acids; Lipophilicity; Nucleosides; Reverse Transcriptase

PMID:
24791029
[PubMed]
PMCID:
PMC4001930
Free PMC Article
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