5 research outputs found
Synthesis and properties of 2′-deoxy-2′,4′-difluoroarabinose-modified nucleic acids
© 2015 American Chemical Society. 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).Peer Reviewe
Synthesis of quaternary aryl phosphonium salts: photoredox-mediated phosphine arylation
We report a synthesis method for the construction of quaternary aryl phoshonium salts at ambient temperature. The regiospecific reaction invovles the coupling of phosphines with aryl radicals derived from diaryliodonium salts under photoredox conditions
Rigid 2′,4′-difluororibonucleosides: Synthesis, conformational analysis, and incorporation into nascent RNA by HCV polymerase
We report on the synthesis and conformational properties of 2′-deoxy-2′,4′-difluorouridine (2′,4′-diF-rU) and cytidine (2′,4′-diF-rC) nucleosides. NMR analysis and quantum mechanical calculations show that the strong stereoelectronic effects induced by the two fluorines essentially ́locḱ the conformation of the sugar in the North region of the pseudorotational cycle. Our studies also demonstrate that NS5B HCV RNA polymerase was able to accommodate 2′,4′-diF-rU 5′-triphosphate (2′,4′-diF-rUTP) and to link the monophosphate to the RNA primer strand. 2′,4′-diF-rUTP inhibited RNA synthesis in dinucleotide-primed reactions, although with relatively high half-maximal inhibitory concentrations (IC50 > 50 μM). 2′,4′- diF-rU/C represents rare examples of ́locked́ ribonucleoside mimics that lack a bicyclic ring structure. © 2014 American Chemical Society.Peer Reviewe
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)