A 6′-Fluoro-Substituent in Bicyclo-DNA Increases Affinity to Complementary RNA Presumably by CF–HC Pseudohydrogen Bonds

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Abstract

The synthesis of a novel bicyclic thymidine analogue carrying a β-fluoro substituent at C6′ (6′F-bcT) has been achieved. Key steps of the synthesis were an electrophilic fluorination/stereospecific hydrogenation sequence of a bicyclo sugar intermediate, followed by an N-iodo-succinimide-induced stereoselective nucleosidation. A corresponding phosphoramidite building block was then prepared and used for oligonucleotide synthesis. Tm measurements of oligonucleotides with single and double incorporations showed a remarkable stabilization of duplex formation particularly with RNA as complement without compromising pairing selectivity. Increases in Tm were in the range of +1–2 °C compared to thymidine and +1–3 °C compared to a standard bc-T residue. Structural investigations of the 6′F-bcT nucleoside by X-ray crystallography showed an in-line arrangement of the fluorine substituent with H6 of thymine, however, with a distance that is relatively long for a nonclassical CF–HC hydrogen bond. In contrast, structural investigations in solution by 1H and 13C NMR clearly showed scalar coupling of fluorine with H6 and C6 of the nucleobase, indicating the existence of at least weak electrostatic interactions. On the basis of these results, we put forward the hypothesis that these weak CF–HC6 electrostatic interactions increase duplex stability by orienting and partially freezing torsion angle χ of the 6′F-bcT nucleoside.

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