Date of Original Version
Biomedical and Pharmaceutical Sciences
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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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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