The initial phosphorylation of nucleosides is the rate-limiting step in the activation of a number of clinically used nucleosides. Anti-HIV nucleoside monophosphates have limited cellular uptake due to the presence of negatively-charged phosphate group. The cycloSaligenyl pronucleotide system has been reported as a masked strategy for intracellular delivery of nucleoside monophosphates. Bis(cycloSaligenyl) derivatives containing two anti-HIV nucleosides, 3'-fluoro-3'-deoxythymidine (FLT) and 3'-azido-3'-deoxythymidine (AZT), were synthesized for potential intracellular delivery of two nucleoside monophosphates. 2,5-Bis(hydroxymethyl)benzene-1,4-diol was selected as a bidentate scaffold and was synthesized by two different methods from bis(methoxymethyl)cyclohexan-1,4-diene-1,4-diol or diethyl 2,5-dihydroxyterephthalate. The reaction of the diol with phosphorous trichloride in the presence of 2,6-lutidine at low temperature, followed by conjugation reaction with the first nucleoside, the reaction of the intermediate with diisopropylphosphoramidous dichloride, conjugation reaction with AZT or FLT, and oxidation afforded bis(cycloSaligenyl) AZT-AZT, FLT-FLT, and FLT-AZT products. 

Synthesis of bis(<i>cyclo</i>Saligenyl) pronucleotides containing two nucleosides from bis(methoxymethyl)benzene-1,4-diol

240th National Meeting (2010)

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Synthesis of bis(cycloSaligenyl) pronucleotides containing two nucleosides from bis(methoxymethyl)benzene-1,4-diol