Synthesis and properties of 2'-deoxy-2',4'-difluoroarabinose-modified nucleic acids.
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).
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
Saúl
S
Martínez-Montero
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
Glen F
GF
Deleavey
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
Arden
A
Dierker-Viik
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
Petra
P
Lindovska
‡Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, 450 Technology Drive, Pittsburgh, Pennsylvania 15219-3143, United States.
Tatiana
T
Ilina
§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.
Guillem
G
Portella
§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.
Modesto
M
Orozco
‡Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, 450 Technology Drive, Pittsburgh, Pennsylvania 15219-3143, United States.
Michael A
MA
Parniak
∥Instituto de Química Física Rocasolano, CSIC, C/ Serrano 119, 28006 Madrid, Spain.
Carlos
C
González
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
Masad J
MJ
Damha
D001089:Arabinose / Q000031:analogs & derivatives* / Q000737:chemistry; D004247:DNA / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D012313:RNA / Q000138:chemical synthesis* / Q000737:chemistry*
C000603249:2'-deoxy-2',4'-difluoroarabinose; D012313:RNA; D004247:DNA; D001089:Arabinose