Ligands with polyfluorophenyl moieties promote a local structural rearrangement in the Spinach2 and Broccoli aptamers that increases ligand affinities

Abstract

The interaction of nucleic acids with their molecular targets often involves structural reorganization that may traverse a complex folding landscape. With the more recent recognition that many RNAs, both coding and noncoding, may regulate cellular activities by interacting with target molecules, it becomes increasingly important to understand the means by which nucleic acids interact with their targets and how drugs might be developed that can influence critical folding transitions. We have extensively investigated the interaction of the Spinach2 and Broccoli aptamers with a library of small molecule ligands modified by various extensions from the imido nitrogen of DFHBI (3,5-difluoro-4-hydroxybenzylidene imidazolinone) that reach out from the Spinach2 ligand binding pocket. Studies of the interaction of these compounds with the aptamers revealed that poly-fluorophenyl-modified ligands initiate a slow change in aptamer affinity that takes an extended time (half-life of ~40 min) to achieve. The change in affinity appears to involve an initial disruption of the entrance to the ligand binding pocket followed by a gradual lockdown for which the most likely driving force is an interaction of the gateway adenine with a nearby 2’OH group. These results suggest that poly-fluorophenyl modifications might increase the ability of small molecule drugs to disrupt local structure and promote RNA remodeling.

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, •C6H5–xFx (2 ≤ x ≤ 4)

“…Fluorophenyl substituents play an important role in novel antibiotic resistance and cancer therapy drugs, 23−26 in addition to improving ligand affinities compared to phenyl substituents. 27,28 These drugs have been shown to have different efficacies when the fluorine is located at different positions on the phenyl substituents. 23 While the structures of fluorophenyl radical reactants can be controlled with leaving groups at the targeted radical position relative to the C−F positions, carbanions may offer another tool in the synthetic toolbox, 29 and our results suggest the potential utility of fluorophenide anions in these syntheses.…”