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

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

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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arabinose / analogs & derivatives*
  • Arabinose / chemistry
  • DNA / chemical synthesis*
  • DNA / chemistry*
  • Molecular Structure
  • RNA / chemical synthesis*
  • RNA / chemistry*

Substances

  • 2'-deoxy-2',4'-difluoroarabinose
  • RNA
  • DNA
  • Arabinose