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J Org Chem. 2015 Mar 20;80(6):3083-91. doi: 10.1021/jo502948t. Epub 2015 Mar 5.

Synthesis and properties of 2'-deoxy-2',4'-difluoroarabinose-modified nucleic acids.

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†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
‡Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, 450 Technology Drive, Pittsburgh, Pennsylvania 15219-3143, United States.
§Joint IRB-BSC program on Computational Biology, Institute for Research in Biomedicine, Barcelona Supercomputing Center, and Department of Biochemistry, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
∥Instituto de Química Física Rocasolano, CSIC, C/ Serrano 119, 28006 Madrid, Spain.


We report the synthesis, thermal stability, and RNase H substrate activity of 2'-deoxy-2',4'-difluoroarabino-modified nucleic acids. 2'-Deoxy-2',4'-difluoroarabinouridine (2,'4'-diF-araU) was prepared in a stereoselective way in six steps from 2'-deoxy-2'-fluoroarabinouridine (2'-F-araU). NMR analysis and quantum mechanical calculations at the nucleoside level reveal that introduction of 4'-fluorine introduces a strong bias toward the North conformation, despite the presence of the 2'-βF, which generally steers the sugar pucker toward the South/East conformation. Incorporation of the novel monomer into DNA results on a neutral to slightly stabilizing thermal effect on DNA-RNA hybrids. Insertion of 2',4'-diF-araU nucleotides in the DNA strand of a DNA-RNA hybrid decreases the rate of both human and HIV reverse transcriptase-associated RNase H-mediated cleavage of the complement RNA strand compared to that for an all-DNA strand or a DNA strand containing the corresponding 2'-F-araU nucleotide units, consistent with the notion that a 4'-fluorine in 2'-F-araU switches the preferred sugar conformation from DNA-like (South/East) to RNA-like (North).

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