Synthesis, anti-HIV and cytostatic evaluation of 3'-deoxy-3'-fluorothymidine (FLT) pro-nucleotides

Winnie Velanguparackel; Nadège Hamon; Jan Balzarini; Christopher McGuigan; Andrew D Westwell

doi:10.1016/j.bmcl.2014.03.092

Synthesis, anti-HIV and cytostatic evaluation of 3'-deoxy-3'-fluorothymidine (FLT) pro-nucleotides

Bioorg Med Chem Lett. 2014 May 15;24(10):2240-3. doi: 10.1016/j.bmcl.2014.03.092. Epub 2014 Apr 5.

Authors

Winnie Velanguparackel¹, Nadège Hamon¹, Jan Balzarini², Christopher McGuigan¹, Andrew D Westwell³

Affiliations

¹ School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK.
² Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
³ School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK. Electronic address: WestwellA@cf.ac.uk.

PMID: 24751439
DOI: 10.1016/j.bmcl.2014.03.092

Abstract

A series of pro-nucleotide phosphoramidates and phosphorodiamidates of the antiviral lead compound 3'-deoxy-3'-fluorothymidine (FLT) have been designed and synthesized. In vitro antiretroviral and cytostatic studies revealed potent (sub-micromolar) inhibition of HIV-1 and HIV-2 replication, with retention of activity in thymidine kinase-negative cell models, as predicted by the ProTide concept.

Keywords: Anticancer; Antiviral; Nucleosides; Phosphoramidates; Pro-drugs; Pro-nucleotides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / pharmacology*
Cytostatic Agents / chemical synthesis*
Cytostatic Agents / pharmacology*
Dideoxynucleosides / chemical synthesis
Dideoxynucleosides / pharmacology
HIV Infections / drug therapy
HIV Infections / virology
HIV-1 / drug effects
Humans
Nucleotides / chemical synthesis*
Nucleotides / pharmacology*

Substances

Anti-HIV Agents
Cytostatic Agents
Dideoxynucleosides
Nucleotides
alovudine