Controlling Dipole Orientation through Curvature: Aromatic Foldamer Bent ß-Sheets and Helix-Sheet-Helix Architectures.

The helix, turn, and ß-strand motifs of biopolymer folded structures have been found to prevail also in non-natural backbones. In contrast, foldamers with aryl rings in their main chains possess distinct conformations that may give access to folded objects beyond the reach of peptidic and nucleotidic backbones. In search of such original architectures, we have explored the effect of bending aromatic amide ß-sheets using building blocks that impart curvature. Cyclic and multiturn noncyclic sequences were synthesized, and their structures were characterized in solution and in the solid state. Stable bent-sheet conformations were shown to prevail in chlorinated solvents. In these structures, folding overcomes intramolecular electrostatic repulsions and forces local dipoles in each layer of the stacked strands to align in a parallel fashion. Sequences having helical segments flanking a central bent aromatic ß-sheet were then synthesized and shown to form well-defined helix-turn-helix architectures in which helical and sheet subcomponents conserve their respective integrity. These objects have a unique basket shape; they possess a cavity the depth and width of which reflects the curvature of the ß-sheet segment. They can be compared to previously described helical closed-shell receptors in which a window has been open, thus providing a means to control guest binding and release pathways and kinetics. As a proof of concept, guest binding to one of the helix-sheet-helix structures is indeed found to be fast on the NMR time scale while it is generally slow in the case of helical capsules.

Assessing stabilization through π-π interactions in aromatic oligoamide ß-sheet foldamers.

We have recently introduced aromatic oligoamide ß-sheet foldamers based on rigid turn units and short linear strands that undergo intramolecular π-π stacking (Sebaoun, L.; Maurizot, V.; Granier, T.; Kauffmann, B.; Huc, I. J. Am. Chem. Soc. 2014, 136, 2168). We now report that conformational stability in these structures can be reached using less rigid turn units and more extensive π-π interactions between longer linear strands. For this study, two-stranded sheets of variable length were prepared. Their conformation was assessed in solution by (1)H NMR and in the solid state by X-ray crystallography.

Aromatic oligoamide ß-sheet foldamers.

A rational approach for the construction of multi-stranded artificial ß-sheets based not on hydrogen bonding, but rather on π-π aromatic stacking, is presented. Using 4,6-dinitro-1,3-phenylenediamine units, rigid turns were designed that allow face-to-face π-π interactions between appended linear aromatic segments to be strong enough for folding in an organic solvent, but weak enough to prevent aggregation and precipitation. Solution and solid-state studies on a series of turn units showed that the desired degree of rigidity, resulting from hindered bond rotation, could be fine-tuned by the inclusion of additional methyl substituents on the aromatic rings. The high degree of preorganization afforded by these qualities further allowed the facile preparation of macrocyclic sheet structures from their noncyclic precursors. These macrocycles were shown to have slow internal dynamics and defined conformational preferences. Using this background, three- and five-stranded artificial ß-sheets were synthesized and their folded conformations extensively characterized in solution by NMR. The solid-state structures of the three- and five-stranded sheets were also elucidated in the solid state by X-ray crystallography and confirmed intramolecular π-π aromatic stacking.

Structural characterizations of oligopyridyl foldamers, α-helix mimetics.

Protein-protein interactions are central to many biological processes, from intracellular communication to cytoskeleton assembly, and therefore represent an important class of targets for new therapeutics. The most common secondary structure in natural proteins is an α-helix. Small molecules seem to be attractive candidates for stabilizing or disrupting protein-protein interactions based on α-helices. In our study, we assessed the ability of oligopyridyl scaffolds to mimic the α-helical twist. The theoretical as well as experimental studies (X-ray diffraction and NMR) on conformations of bipyridines in the function of substituent and pyridine nitrogen positions were carried out. Furthermore, the experimental techniques showed that the conformations observed in bipyridines are maintained within a longer oligopyridyl scaffold (quaterpyridines). The alignment of the synthesized quaterpyridine with two methyl substituents showed that it is an α-helix foldamer; their methyl groups overlap very well with side chain positions, i and i + 3, of an ideal α-helix.