Synthesis and properties of 6'-fluoro-tricyclo-DNA.

Abstract

The synthesis of the two fluorinated tricyclic nucleosides 6'-F-tc-T and 6'-F-tc-5(Me)C, as well as the corresponding building blocks for oligonucleotide assembly, was accomplished. An X-ray analysis of N(4)-benzoylated 6'-F-tc-(5Me)C reavealed a 2'-exo (north) conformation of the furanose ring, characterizing it as an RNA mimic. In contrast to observations in the bicyclo-DNA series, no short contact between the fluorine atom and the H6 of the base, reminiscent of a nonclassical F···H hydrogen bond, could be observed. Tm measurements of modified oligodeoxynucleotides with complementary RNA showed slightly sequence-dependent duplex stabilization profiles with maximum ΔTm/mod values of +4.5 °C for 6'-F-tc-(5Me)C and +1 °C for 6'-F-tc-T. In comparison with parent tc-modified oligonucleotides, no relevant changes in Tm were detected, attributing the fluorine substituent a neutral role in RNA affinity. A structural analysis of duplexes with DNA and RNA by CD-spectroscopy revealed a shift from B- to A-type conformation induced by the 6'-F-tc-nucleosides. This is not a specific "fluorine effect", as the same is also observed for the parent tc-modifications. The two fluorinated tc-nucleosides were also incorporated into a pure tricyclo-DNA backbone and showed no discrimination in Tm with complementary RNA, demonstrating that 6'-F substitution is also compatible within fully modified tc-oligonucleotides.