Synthesis and Structural Characterization of 2′‐Fluoro‐α‐L‐RNA‐Modified Oligonucleotides

Abstract

We describe the synthesis and binding properties of oligonucleotides that contain one or more 2'-fluoro-α-L-RNA thymine monomer(s). Incorporation of 2'-fluoro-α-L-RNA thymine into oligodeoxynucleotides decreased thermal binding stability slightly upon hybridization with complementary DNA and RNA with the smallest destabilization towards RNA. Thermodynamic data show that the duplex formation with 2'-fluoro-α-L-RNA nucleotides is enthalpically disfavored but entropically favored. 2'-Fluoro-α-L-RNA nucleotides exhibit very good base pairing specificity following Watson--Crick rules. The 2'-fluoro-α-L-RNA monomer was designed as a monocyclic mimic of the bicyclic α-L-LNA, and molecular modeling showed that this indeed is the case as the 2'-fluoro monomer adopts a C3'-endo/C2'-exo sugar pucker. Molecular modeling of modified duplexes show that the 2'-fluoro-α-L-RNA nucleotides partake in Watson--Crick base pairing and nucleobase stacking when incorporated in duplexes while the unnatural α-L-ribo configured geometry of the sugar is absorbed by changes in the sugar-phosphate backbone torsion angles. The duplex behavior of our new nucleotide follows that of α-L-LNA, by and large.

Synthesis and Structural Characterization of 2′-Deoxy-2′-fluoro-l-uridine Nucleic Acids

“…Indeed, the modified l -DNA presents great structural stability, as evidenced by the overall and local parameters in the l -helix. Although the l -type 2′-F-uridine monomer and its oligonucleotide have been pioneered before, our study here for the first time comprehensively demonstrates its superiority and provides the structural foundation. Therefore, these findings will provide the theoretical framework for the l -nucleic acid therapy design where thermostability is important, including the l -aptamer for disease treatment, l -nanoparticle for drug delivery, and l -molecular beacon for diagnosis.…”

Synthesis and Structural Characterization of 2′‐Deoxy‐2′‐Methoxy‐L‐Cytidine Nucleic Acids

“…[24,27] Besides, the fluoro-modifications have also been successfully introduced into the 2'-position of Ldeoxyribose of pyrimidines by our [28,29] and other labs. [30][31][32][33] In general, a greater number of chemical derivatizations are required to fully exploit the potent of L -nucleic acids as a technology. Considering the functional significance of 2'-OMe modification to nucleic acid molecules, we decide to extend our earlier research by utilizing chemical synthesis to produce L -type 2'-deoxy-2'-methoxycytidine nucleosides and their oligonucleotides.…”

“…To date, the reported modified L ‐nucleic acids include the utilization of L ‐5‐aminoallyl‐uridine, which has the chemical moiety at 5‐position of uridine that plays a critical role for molecular interaction [24,27] . Besides, the fluoro‐modifications have also been successfully introduced into the 2′‐position of L ‐deoxyribose of pyrimidines by our [28,29] and other labs [30–33] . In general, a greater number of chemical derivatizations are required to fully exploit the potent of L ‐nucleic acids as a technology.…”