Synthesis and Properties of 6′-Fluoro-tricyclo-DNA

The synthesis of the two fluorinated
tricyclic nucleosides 6′-F-tc-T
and 6′-F-tc-5MeC, 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. 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-5MeC 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.