C4'-Fluorinated Oligodeoxynucleotides: Synthesis, Stability, Structural Studies

Fluoro-substitution on the ribose moiety (e. g., 2'-F-deoxyribonucleotide) represents a popular way to modulate the ribose conformation and, hence, the structure and function of nucleic acids. In the present study, we synthesized 4'-F-deoxythymidine (^4'-F T) and introduced it to oligodeoxyribonucleotides (ODNs). Though scission of the glycosylic bond of ^4'-F T followed by strand cleavage occurred to some extent under alkaline conditions, the ^4'-F T-modified ODNs were rather stable in neutral buffers. NMR studies showed that like 2'-F-deoxyribonucleoside, ^4'-F T exists predominantly in the North conformation not only in the nucleoside form but also in the context of ODN strands. Circular dichroism spectroscopy, thermal denaturing and RNase H1 footprinting studies of ^4'-F T-modified ODN/cDNA and ODN/cRNA duplexes indicated that the North conformation tendency of ^4'-F T is maintained in the duplexes, leading to a local structural perturbation. Collectively, 4'-F-deoxyribonucleotide structurally resembles the 2'-F-deoxyribonucleotide but imparts less structural perturbation to the duplex than the latter.