Aromatic Oligoamide Research Articles

Redox-Regulated and Guest-Driven Transformations of Aromatic Oligoamide Foldamers in Advanced Structures.

In this study, we demonstrate that an aromatic oligoamide sequence assembles into a trimeric helix-turn-helix architecture with a disulfide linkage, and upon cleavage of this linkage, it reconstructs into an antiparallel double helix. The antiparallel double helix is accessible to encapsulate a diacid guest within its cavity, forming a 2:1 host-guest complex. In contrast, hydrogen-bonding interactions between the trimeric-assembled structure and guests induce a conformational shift in the trimeric helix, resulting in a cross-shaped double-helix complex at a 2:2 host-guest ratio. Interconversions between the trimeric helix and the antiparallel double helix, along with their respective host-guest complexes, can be initiated through thiol/disulfide redox-mediated regulation.

Is Simultaneous Binding to DNA and Gyrase Important for the Antibacterial Activity of Cystobactamids?

Cystobactamids are aromatic oligoamides that exert their natural antibacterial properties by inhibition of bacterial gyrases. Such aromatic oligoamides were proposed to inhibit α-helix-mediated protein-protein interactions and may serve for specific recognition of DNA. Based on this suggestion, we designed new derivatives that have duplicated cystobactamid triarene units as model systems to decipher the specific binding mode of cystobactamids to double stranded DNA. Solution NMR analyses revealed that natural cystobactamids as well as their elongated analogues show an overall bent shape at their central aliphatic unit, with an average CX-CY-CZ angle of ~110 degrees. Our finding is corroborated by the target-bound structure of close analogues, as established by cryo-EM very recently. Cystobactamid CN-861-2 binds directly to the bacterial gyrase with an affinity of 9 μM, and also exhibits DNA-binding properties with specificity for AT-rich DNA. Elongation/dimerization of the triarene subunit of native cystobactamids is demonstrated to lead to an increase in DNA binding affinity. This implies that cystobactamids' gyrase inhibitory activity necessitates not just interaction with the gyrase itself, but also with DNA via their triarene unit.

Enhancing the Features of DNA Mimic Foldamers for Structural Investigations.

DNA mimic foldamers based on aromatic oligoamide helices bearing anionic phosphonate side chains have been shown to bind to DNA-binding proteins sometimes orders of magnitude better than DNA itself. Here, we introduce new features in the DNA mimic foldamers to facilitate structural investigations of their interactions with proteins. Thirteen new foldamer sequences have been synthesized and characterized using NMR, circular dichroism, molecular modeling, and X-ray crystallography. The results show that foldamer helix handedness can be quantitatively biased by means of a single stereogenic center, that the foldamer structure can be made C2-symmetrical as in palindromic B-DNA sequences, and that associations between foldamer helices can be promoted utilizing dedicated C-terminal residues that act as sticky ends in B-DNA structures.

Solvent dependent hierarchical dual helicity in a fused [4]carbohelicene/quinoline oligoamide foldamer

Two classes of helical motif, namely a [4]carbohelicene and an aromatic oligoamide foldamer, were fused to form a hybrid molecular construct in which their helical axes are parallel.

Photon-gated foldaxane assembly/disassembly.

Integrating multiple anthracene motifs into aromatic oligoamide sequences gives rise to photoactive foldamers that can sequester a molecular thread forming helix-on-axle assemblies. Photoirradiation is shown to distort the helical host and drive dissociation of the supramolecular assembly and thread liberation as signalled by a photonic output, while thermal reversion regenerates the assembly.

Interrogating the potential of helical aromatic foldamers for protein recognition.

A biotinylated helical aromatic oligoamide foldamer equivalent in size to a 24mer peptide was designed without any prejudice other than to display various polar and hydrophobic side chains at its surface. It was synthesized on solid phase, its P- and M-helical conformers were separated by HPLC on a chiral stationary phase, and the solid state structure of a non-biotinylated analogue was elucidated by X-ray crystallography. Pull-down experiments from a yeast cell lysate using the foldamer as a bait followed by proteomic analysis revealed potential protein binding partners. Three of these proteins were recombinantly expressed. Biolayer interferometry showed submicromolar binding demonstrating the potential of a given foldamer to have affinity for certain proteins in the absence of design considerations. Yet, binding selectivity was low in all three cases since both P- and M-conformers bound to the proteins with similar affinities.

High‐Affinity Hybridization of Complementary Aromatic Oligoamide Strands in Water

AbstractWe prepared a series of water‐soluble aromatic oligoamide sequences all composed of a segment prone to form a single helix and a segment prone to dimerize into a double helix. These sequences exclusively assemble as antiparallel duplexes. The modification of the duplex inner rim by varying the nature of the substituents borne by the aromatic monomers allowed us to identify sequences that can hybridize by combining two chemically different strands, with high affinity and complete selectivity in water. X‐ray crystallography confirmed the expected antiparallel configuration of the duplexes whereas NMR spectroscopy and mass spectrometry allowed us to assess precisely the extent of the hybridization. The hybridization kinetics of the aromatic strands was shown to depend on both the nature of the substituents responsible for strand complementarity and the length of the aromatic strand. These results highlight the great potential of aromatic hetero‐duplex as a tool to construct non‐symmetrical dynamic supramolecular assemblies.

High-Affinity Hybridization of Complementary Aromatic Oligoamide Strands in Water.

We prepared a series of water-soluble aromatic oligoamide sequences all composed of a segment prone to form a single helix and a segment prone to dimerize into a double helix. These sequences exclusively assemble as antiparallel duplexes. The modification of the duplex inner rim by varying the nature of the substituents borne by the aromatic monomers allowed us to identify sequences that can hybridize by combining two chemically different strands, with high affinity and complete selectivity in water. X-ray crystallography confirmed the expected antiparallel configuration of the duplexes whereas NMR spectroscopy and mass spectrometry allowed us to assess precisely the extent of the hybridization. The hybridization kinetics of the aromatic strands was shown to depend on both the nature of the substituents responsible for strand complementarity and the length of the aromatic strand. These results highlight the great potential of aromatic hetero-duplex as a tool to construct non-symmetrical dynamic supramolecular assemblies.

Optimization and Automation of Helical Aromatic Oligoamide Foldamer Solid-Phase Synthesis.

Helically folded oligoamides of 8-amino-2-quinolinecarboxylic acid composed of up to 41 units were prepared using optimized manual solid-phase synthesis (SPS). The high yield and purity of the final products places these SPS protocols among the most efficient known to date. Furthermore, analytical methods allowing for the clear identification and purity assessment of the products were validated, including 1 H NMR, a seldom used method for such large molecules. Adaption of the SPS protocols, in particular using in situ acid chloride activation under Appel's conditions, made it possible to efficiently implement SPS on a commercial peptide synthesizer, leading to a dramatic reduction of the laboratory work required to produce long sequences. Automation constitutes a breakthrough for the development of helical aromatic oligoamide foldamers.

Homochiral versus Heterochiral Dimeric Helical Foldamer Bundles: Chlorinated-Solvent-Dependent Self-Sorting.

Aromatic oligoamide sequences programmed to fold into stable helical conformations were designed to display a linear array of hydrogen-bond donors and acceptors at their surface. Sequences were prepared by solid-phase synthesis. Solution 1 H NMR spectroscopic studies and solid-state crystallographic structures demonstrated the formation of stable hydrogen-bond-mediated dimeric helix bundles that could be either heterochiral (with a P and an M helix) or homochiral (with two P or two M helices). Formation of the hetero- or homochiral dimers could be driven quantitatively using different chlorinated solvents-exemplifying a remarkable case of either social or narcissistic chiral self-sorting or upon imposing absolute handedness to the helices to forbid PM species.

Combining local conformational preferences and solvophobic effects in helical aromatic oligoamide foldamers.

Aromatic oligoamide foldamers were designed using a newly-developed monomer so that helical folding was promoted by both local conformation preferences and solvophobic effects. Solid phase synthesis provided quick access to the desired sequences. Sharp solvent-driven conformational transitions that depended on sequence length were evidenced by both NMR and UV absorption spectroscopies.

High-affinity single and double helical pseudofoldaxanes with cationic guests.

Two aromatic oligoamides, the 8-residue H8 and 16-residue H16, that adopt stable, cavity-containing helical conformations were examined for their complexation of a rodlike dicationic guest, octyl viologen (OV2+) and para-bis(trimethylammonium)benzene (TB2+). Studies based on 1D and 2D 1H NMR, isothermal titration calorimetry (ITC), and X-ray crystallography demonstrated that H8 and H16 wraps around two OV2+ ions as a double helix and a single helix, respectively, resulting in 2 : 2 and 1 : 2 complexes. Compared to H8, the longer H16 binds the OV2+ ions with much higher binding affinity and with extraordinary negative cooperativity. In contrast to its 1 : 2 binding with OV2+, the binding of helix H16 with the bulkier guest TB2+ shows a 1 : 1 ratio. Host H16 also selectively binds OV2+ in the presence of TB2+. This novel host-guest system features pairwise placement of the otherwise strongly repulsive OV2+ ions in the same cavity, strong negative cooperativity, and mutual adaptability of hosts and guests. The resultant complexes are highly stable [2]-, [3]-, and [4]pseudo-foldaxanes with few known precedents.

Controlling aromatic helix dimerization in water by tuning charge repulsions.

Several helically folded aromatic oligoamides were designed and synthesized. The sequences were all water-soluble thanks to the charged side chains borne by the monomers. Replacing a few, sometimes only two, charged side chains by neutral methoxy groups was shown to trigger the formation of various aggregates which could be tentatively assigned to head-to-head stacked dimers of single helices, double helical duplexes and a quadruplex, none of which would form in organic solvent with organic-soluble analogues. The nature of the aggregates was supported by concentration and solvent dependent NMR studies, 1H DOSY experiments, mass spectrometry, and X-ray crystallography or energy-minimized models, as well as analogies with earlier studies. The hydrophobic effect appears to be the main driving force for aggregation but it can be finely modulated by the presence or absence of a small number of charges to an extent that had no precedent in aromatic foldamer architectures. These results will serve as a benchmark for future foldamer design in water.

Ultra-Tight Host-Guest Binding with Exceptionally Strong Positive Cooperativity.

Cooperativity plays a critical role in self-assembly and molecular recognition. A rigid aromatic oligoamide macrocycle with a cyclodirectional backbone binds with DABCO-based cationic guests in a 2 : 1 ratio in high affinities (Ktotal ≈1013 M-2 ) in the highly polar DMF. The host-guest binding also exhibits exceptionally strong positive cooperativity quantified by interaction factors α that are among the largest for synthetic host-guest systems. The unusually strong positive cooperativity, revealed by isothermal titration calorimetry (ITC) and fully corroborated by mass spectrometry, NMR and computational studies, is driven by guest-induced stacking of the macrocycles and stabilization from the alkyl end chains of the guests, interactions that appear upon binding the second macrocycle. With its tight binding driven by extraordinary positive cooperativity, this host-guest system provides a tunable platform for studying molecular interactions and for constructing stable supramolecular assemblies.

Ultra‐Tight Host‐Guest Binding with Exceptionally Strong Positive Cooperativity

AbstractCooperativity plays a critical role in self‐assembly and molecular recognition. A rigid aromatic oligoamide macrocycle with a cyclodirectional backbone binds with DABCO‐based cationic guests in a 2 : 1 ratio in high affinities (Ktotal ≈1013 M−2) in the highly polar DMF. The host–guest binding also exhibits exceptionally strong positive cooperativity quantified by interaction factors α that are among the largest for synthetic host–guest systems. The unusually strong positive cooperativity, revealed by isothermal titration calorimetry (ITC) and fully corroborated by mass spectrometry, NMR and computational studies, is driven by guest‐induced stacking of the macrocycles and stabilization from the alkyl end chains of the guests, interactions that appear upon binding the second macrocycle. With its tight binding driven by extraordinary positive cooperativity, this host–guest system provides a tunable platform for studying molecular interactions and for constructing stable supramolecular assemblies.

Directing the Self-Assembly of Aromatic Foldamer Helices using Acridine Appendages and Metal Coordination.

Folded molecules provide complex interaction interfaces amenable to sophisticated self-assembly motifs. Because of their high conformational stability, aromatic foldamers constitute suitable candidates for the rational elaboration of self-assembled architectures. Several multiturn helical aromatic oligoamides have been synthesized that possess arrays of acridine appendages pointing in one or two directions. The acridine units were shown to direct self-assembly in the solid state via aromatic stacking leading to recurrent helix-helix association patterns under the form of discrete dimers or extended arrays. In the presence of Pd(II), metal coordination of the acridine units overwhelms other forces and generates new metal-mediated multihelical self-assemblies, including macrocycles. These observations demonstrate simple access to different types of foldamer-containing architectures, ranging from discrete objects to 1D and, by extension, 2D and 3D arrays.

Optimization of an Asymmetric Reaction.

Invited for the cover of this issue are Quan Gan and co-workers at the Huazhong University of Science and Technology. The image depicts aromatic oligoamide sequences winding around a substrate with conformational control. Read the full text of the article at 10.1002/chem.202200834.

Front Cover: Optimization of an Asymmetric Reaction in the Cavity of Chiral Aromatic Oligoamide Foldamers (Chem. Eur. J. 28/2022)

Front Cover: Optimization of an Asymmetric Reaction in the Cavity of Chiral Aromatic Oligoamide Foldamers (Chem. Eur. J. 28/2022)

Generalizing the Aromatic δ-Amino Acid Foldamer Helix.

A series of aromatic oligoamide foldamer sequences containing different proportions of three δ‐amino acids derived from quinoline, pyridine, and benzene and possessing varying flexibility, for example due to methylene bridges, were synthesized. Crystallographic structures of two key sequences and 1H NMR data in water concur to show that a canonical aromatic helix fold prevails in almost all cases and that helix stability critically depends on the ratio between rigid and flexible units. Notwithstanding subtle variations of curvature, i. e. the numbers of units per turn, the aromatic δ‐peptide helix is therefore shown to be general and tolerant of a great number of sp3 centers. We also demonstrate canonical helical folding upon alternating two monomers that do not promote folding when taken separately: folding occurs with two methylenes between every other unit, not with one methylene between every unit. These findings highlight that a fine‐tuning of helix handedness inversion kinetics, curvature, and side chain positioning in aromatic δ‐peptidic foldamers can be realized by systematically combining different yet compatible δ‐amino acids.

Optimization of an Asymmetric Reaction in the Cavity of Chiral Aromatic Oligoamide Foldamers.

An asymmetric reaction can be implemented and refined in the helical cavity of aromatic oligoamide sequences. These sequences, which bear a chiral inducer, can fold into helical structures with absolute control of the helical sense, whereby a ketone substrate covalently linked in the cavity can be asymmetrically reduced to diastereomers. The diastereoselectivity of the reduction is highly dependent on the shielding efficiency of the helical cavity. Iterative modifications of the sequence, such as addition and replacement of monomers, can fine-tune the cavity to realize the asymmetric reaction, thereby progressively increasing the diastereomeric excess up to 90 %.