Synthesis and anti-HIV activities of bis-(cyclo Saligenyl) pronucleotides derivatives of 3'-fluoro-3'-deoxythymidine and 3'-azido-3'-deoxythymidine

Yousef Ahmadibeni; Rakesh Tiwari; Chelsie Swepson; Jui Pandhare; Chandravanu Dash; Gustavo F Doncel; Keykavous Parang

doi:10.1016/j.tetlet.2010.12.038

Synthesis and anti-HIV activities of bis-(cyclo Saligenyl) pronucleotides derivatives of 3'-fluoro-3'-deoxythymidine and 3'-azido-3'-deoxythymidine

Tetrahedron Lett. 2011 Feb 16;52(7):802-805. doi: 10.1016/j.tetlet.2010.12.038. Epub 2010 Dec 15.

Authors

Yousef Ahmadibeni¹, Rakesh Tiwari², Chelsie Swepson³, Jui Pandhare³, Chandravanu Dash³, Gustavo F Doncel⁴, Keykavous Parang²

Affiliations

¹ Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI 02881, USA ; Department of Chemistry, Columbus State University, Columbus, GA 31907, USA.
² Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI 02881, USA.
³ Centre for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA.
⁴ CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA.

Abstract

Anti-HIV nucleoside monophosphates have limited cellular uptake due to the presence of negatively-charged phosphate group. Bis-(cycloSaligenyl) derivatives containing two anti-HIV nucleosides, 3'-fluoro-3'-deoxythymidine (FLT) and 3'-azido-3'-deoxythymidine (AZT) were synthesized to increase intracellular delivery of nucleoside monophosphates. 2,5-Bis(hydroxymethylene)benzene-1,4-diol was selected as a monocyclic bidentate scaffold and synthesized by three different methods from bis(hydroxymethylene)cyclohexan-1,4-diene-1,4-diol, or diethyl 2,5-dihydroxyterephthalate. The reaction of the tetraol with diisopropylphosphoramidous dichloride in the presence of 2,6-lutidine, followed by conjugation reactions with nucleosides (i.e., FLT and AZT) and oxidation afforded symmetrical and unsymmetrical bis-(cycloSaligenyl) diphosphate triester products, AZT-AZT, FLT-FLT, and FLT-AZT conjugates, in 63-74% overall yields and modest anti-HIV activities (IC₅₀ = 2.8-69.6 µM).

Keywords: AZT; Anti-HIV; Bis-(cycloSaligenyl); FLT; Nucleosides.

Abstract

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