C2′-F Stereoconfiguration As a Puckering Switch for Base Stacking at the Dinucleotide Level

Abstract

Fluorine configuration at C2' of the bis(2'-fluorothymidine) dinucleotide is demonstrated to drive intramolecular base stacking. 2'-β F-Configuration drastically reduces stacking compared to the 2'-α series. Hence, base stacking emerges as being tunable by the C2'-F stereoconfiguration through dramatic puckering variations scrutinized by NMR and natural bond orbital analysis. Accordingly, 2'-β F-isomer photoreactivity is significantly reduced compared to that of the 2'-α F-isomer.

High-Throughput Screening for Ultrafast Photochemical Reaction Discovery

“…Furthermore, the observed change is in opposition to our hypothesis that a longer-lived excited-state lifetime correlates with a higher CPD yield, therefore lending further credence to the suggested stacking effect by Moriou and co-workers. 30,31 Nonetheless and rather interestingly, we have observed a link between sugar modification and excited-state lifetime. There are a variety of ground-state conformers in thymidine, the relative populations of which are known to change as a function of structural modification, 34,35 and the current result suggests that ground-state conformational diversity may be projected onto the excited state in a way that markedly affects the excited-state dynamics.…”

“…27−29 In addition, studies have shown that fluorination at the C2′ position of the sugar ring changes CPD yield: fluorination at the exo position increases the yield, while fluorination at the endo position decreases the yield. 30,31 Speculation about this mechanism has been limited to the sugar conformation affecting the stacking of the bases within the sequence, thus positioning adjacent bases to be closer or further at the moment of excitation. We are interested in whether the excited-state lifetime of the nucleoside alone is modified by the conformation of the sugar when in isolation and this effect instead can play the determining role in defining the CPD yield.…”

“…Second, despite the strong trend in the literature CPD yield with changing sugar conformation only exo -F thymidine has a distinctly different excited-state lifetime. Furthermore, the observed change is in opposition to our hypothesis that a longer-lived excited-state lifetime correlates with a higher CPD yield, therefore lending further credence to the suggested stacking effect by Moriou and co-workers. , …”

Manipulating DNA G‐Quadruplex Structures by Using Guanosine Analogues

“…Another popular anti ‐G substitute is based on the C2′ epimer of F rG, 2′‐deoxy‐2′‐fluoroarabinoguanosine ( F araG). Steered by strong gauche and possibly also steric effects due to the β‐2′‐fluorine, this rather rigid nucleoside tends to adopt a more DNA‐like south‐east/east or C1′‐ exo /O4′‐ endo conformation . Nevertheless, expected unfavorable interactions between the β‐positioned fluorine above the furanose sugar and a syn ‐guanine moiety, together with a potential unconventional intranucleotide hydrogen bond between fluorine and H8 of an anti ‐guanine base, may be advocated as major determinants for its preferred anti conformation …”

SN- and NS-puckered sugar conformers are precursors of the (6–4) photoproduct in thymine dinucleotide

“…13,14 The most recurrent, but rather imprecise conformational factor associated with (6–4) PP formation is the requirement of a certain degree of flexibility of the sugar phosphate DNA backbone. Experimental 15 and theoretical 16 studies have also led to identify the nucleotide sugar conformation as a major determinant in the production of (6–4) adduct at the single-strand di- and oligonucleotide level. However, further experimental studies are still required to provide an in-depth understanding of the role played by the sugar conformation in (6–4) PP production.…”