title: Synthesis and anti-HIV activities of bis-(cycloSaligenyl) pronucleotides derivatives of 3'-fluoro-3'-deoxythymidine and 3'-azido-3'-deoxythymidine.
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).
authors.affiliation: 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.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Ahmadibeni
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Tiwari
authors.affiliation: Centre for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Chelsie
authors.initials: C
authors.lastname: Swepson
authors.affiliation: Centre for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Jui
authors.initials: J
authors.lastname: Pandhare
authors.affiliation: Centre for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Chandravanu
authors.initials: C
authors.lastname: Dash
authors.affiliation: CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Doncel
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
keywords: AZT; Anti-HIV; Bis-(cycloSaligenyl); FLT; Nucleosides