Synthesis and anti-HIV activities of bis-(cycloSaligenyl) pronucleotides derivatives of 3′-fluoro-3′-deoxythymidine and 3′-azido-3′-deoxythymidine

Authors

Yousef Ahmadibeni, University of Rhode Island
Rakesh Tiwari, University of Rhode Island
Chelsie Swepson
Jui Pandhare
Chandravanu Dash
Gustavo F. Doncel
Keykavous Parang, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

2011

Department

Biomedical and Pharmaceutical Sciences

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).

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Citation/Publisher Attribution

Ahmadibeni, Y., Tiwari, R., Swepson, C., Pandhare, J., Dash, C., Doncel, G. F., & Parang, K. (2011). Synthesis and anti-HIV activities of bis-(cycloSaligenyl) pronucleotides derivatives of 3′-fluoro-3′-deoxythymidine and 3′-azido-3′-deoxythymidine. Tetrahedron Letters, 52(7), 802-805. doi: 10.1016/j.tetlet.2010.12.038

Available at: https://doi.org/10.1016/j.tetlet.2010.12.038

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