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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.

Author information

1
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
2
‡Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, 450 Technology Drive, Pittsburgh, Pennsylvania 15219-3143, United States.
3
§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.
4
∥Instituto de Química Física Rocasolano, CSIC, C/ Serrano 119, 28006 Madrid, Spain.

Abstract

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).

PMID:
25723361
PMCID:
PMC4484724
DOI:
10.1021/jo502948t
[Indexed for MEDLINE]
Free PMC Article

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