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^MeC, as well as the corresponding building blocks for oligonucleotide assembly, was accomplished. An X-ray analysis of N⁴-benzoylated 6′-F-tc-^5MeC 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. <i>T</i>_m measurements of modified oligodeoxynucleotides with complementary RNA showed slightly sequence-dependent duplex stabilization profiles with maximum Δ<i>T</i>_m/mod values of +4.5 °C for 6′-F-tc-^5MeC and +1 °C for 6′-F-tc-T. In comparison with parent tc-modified oligonucleotides, no relevant changes in <i>T</i>_m 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 <i>T</i>_m with complementary RNA, demonstrating that 6′-F substitution is also compatible within fully modified tc-oligonucleotides