Design, synthesis, antiviral and cytostatic evaluation of novel isoxazolidine nucleotide analogues with a 1,2,3-triazole linker

Azidation (TMSN3, SnCl4) of a 9:1 mixture of trans- and cis-5-acetoxy-2-methylisoxazolidin-3-yl-3-phosphonates at the anomeric carbon atom led to the formation of the equimolar mixture of cis- and trans-5-azido-2-methylisoxazolidin-3-yl-3-phosphonates, which were efficiently separated. The 1,3-dipolar cycloaddition of pure trans- and cis-5-azidoisoxazolidin-3-yl-3-phosphonates with selected alkynes gave the respective nucleoside mimetics containing a 1,2,3-triazole linker. The (1,2,3-triazolyl)isoxazolidine phosphonates obtained herein were evaluated in vitro for activity against a variety of DNA and RNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations. Compounds 15f–j and 16f–j were cytostatic in the higher micromolar range.

Inhibitory activity of cell proliferation for HEL cells as well as L1210, CEM and HeLa cells of several (1,2,3-triazolyl)isoxazolidine phosphonates was evaluated. The unsubstituted and fluoro-substituted phenyl derivatives appeared cytostatic (CC50 40–250 μM).Figure optionsDownload as PowerPoint slideHighlights
► An isoxazolidine-3-yl-3-phosphonate skeleton and nucleobases linked by 1,2,3-triazole.
► Efficient azidation of 5-acetoxy-2-methylisoxazolidin-3-yl-3-phosphonates.
► Nucleoside mimetics from 5-azido-2-methylisoxazolidin-3-yl-3-phosphonates.
► Cytostatic substituted (1,2,3-triazolyl)isoxazolidine phosphonates.