Carbohydrate-derived conformationally restricted bicyclic dipeptides as potential hetero foldamer building blocks

Starting from carbohydrate precursors, hetero foldamer building blocks featuring diverse amino acid side chains and stereochemistry have been accessed via a multi-step synthetic protocol. These conformationally restricted bicyclic dipeptide building blocks are characterized by a constrained β-lactam ring fused with a pyrrolidine ring carrying a hydroxyethylamine isostere (HEA) on the backbone. These building blocks offer the possibility of developing foldamers with interesting structural architectures, conspicuously different from those classically observed. Furthermore, such hetero-building blocks have the potential to augment the conformational space available for foldamer design with diverse backbone conformations and structural architectures.     

Oligo-Quinolylene–Vinylene Foldamers

Quinoline based aromatic amide foldamers are known to adopt stable folded conformations. We have developed a synthetic approach to produce similar oligomers where all amide bonds, or part of them, have been replaced by an isosteric vinylene group. The results of solution and solid state structural studies show that oligomers exclusively containing vinylene linkages are not well folded, and adopt predominantly flat conformations. In contrast, a vinylene segment flanked by helical oligoamides also folds in a helix, albeit with a slightly lower curvature. The presence of vinylene functions also result in an extension of π-conjugation across the oligomer that may change charge transport properties. Altogether, these results pave the way to foldamers in which both structural control and specific electronic properties may be engineered.     

Secondary structural preferences of 2,2-disubstituted pyrrolidine-4-carboxylic acid oligomers: beta-peptide foldamers that cannot form internal hydrogen bonds

We examine a new class of beta-peptides, 2,2-disubstituted pyrrolidine-4-carboxylic acid oligomers, and show that they manifest discrete conformational preferences despite the impossibility of internal hydrogen bonding. Numerous beta-peptide families have been described that display specific secondary structural preferences, but all of the conformations characterized in detail so far have contained internal hydrogen bonds. Internal hydrogen bonding is observed within the most common secondary structures of conventional peptides as well. Identifying foldamers in which shape control is independent of hydrogen bonding is significant in two ways. At a fundamental level, foldamers in this small but growing class are interesting because their shapes are controlled by distinctive networks of noncovalent forces. At a practical level, non-hydrogen bonded foldamers may be useful in biomedical applications because the low intrinsic polarity of their backbones may promote bioavailability.     

Spin system assignment of homo-o-phenylene ethynylene oligomers

We previously reported the synthesis and solution characterization of short o-phenylene ethynylene (oPE) foldamers. Proton correlation techniques are not adequate for NMR assignment in these compounds as the ethynylene linkers interrupt proton connectivity. In order to facilitate structural characterization and more fully harness the power of NMR, it is necessary to know the sequence of spin systems along the molecular backbone. For example, spin system assignment is required to unambiguously assign NOE correlations for structural determination of folded forms in solution. Therefore, we developed a method to assign the aromatic spin systems in these compounds using HMBC experiments. This has been performed for tetrameric (Es4), pentameric (Es5), and hexameric (Es6) oligomers and is expected to prove useful for this class of foldamers in general. The proton assignments obtained by this technique have been useful toward confirming the previous hypotheses of helical folding in oPE systems.     

Design of Oligourea-Based Foldamers with Antibacterial and Antifungal Activities

There is an urgent need to develop new therapeutic strategies to fight the emergence of multidrug resistant bacteria. Many antimicrobial peptides (AMPs) have been identified and characterized, but clinical translation has been limited partly due to their structural instability and degradability in physiological environments. The use of unnatural backbones leading to foldamers can generate peptidomimetics with improved properties and conformational stability. We recently reported the successful design of urea-based eukaryotic cell-penetrating foldamers (CPFs). Since cell-penetrating peptides and AMPs generally share many common features, we prepared new sequences derived from CPFs by varying the distribution of histidine- and arginine-type residues at the surface of the oligourea helix, and evaluated their activity on both Gram-positive and Gram-negative bacteria as well as on fungi. In addition, we prepared and tested new amphiphilic block cofoldamers consisting of an oligourea and a peptide segment whereby polar and charged residues are located in the peptide segment and more hydrophobic residues in the oligourea segment. Several foldamer sequences were found to display potent antibacterial activities even in the presence of 50% serum. Importantly, we show that these urea-based foldamers also possess promising antifungal properties.     

Hydrogen bonding-induced aromatic oligoamide foldamers as spherand analogues to accelerate the hydrolysis of nitro-substituted anisole in aqueous media

Four intramolecular hydrogen bonding-driven aromatic amide foldamers 2-5 have been designed and synthesized in which a 2-methoxy-3-nitrobenzamide unit was incorporated at the end of the backbone. Kinetic studies in dioxane-water (4:1, v/v) at 60-90 degrees C have revealed that the folded backbone of the oligomers was, like the rigidified spherand, able to complex Li+, Na+, and K+ and, consequently, accelerated the hydrolysis of the nitro-appended anisole unit of the foldamers. Generally, longer foldamers displayed an increased accelerating effect, and LiOH displayed the highest reactivity probably due to the most efficient complexation by the folded oligomers. Addition of excessive potassium chloride substantially reduced the complexing interaction, and the hydrolysis of the longer oligomers became slower than that of the shorter ones due to an increased steric effect. The results indicate that, even in a hot aqueous medium of high polarity, intramolecular hydrogen bonding is still able to induce structurally matched oligomers to generate a preorganized rigidified conformation.     

BINOL-based foldamers--access to oligomers with diverse structural architectures

In this article, we report on the synthesis and conformation of a new family of aromatic oligoamide foldamers based on binaphthol (BINOL) monomers. A series of oligomers with differing chirality of the individual BINOL building blocks and mixed sequences of alternate BINOL and pyridyl building blocks has been synthesized and structurally characterized. NMR and quantum chemical calculations on the basis of ab initio MO theory were performed to obtain insight into the conformational features of these oligomers. It is shown that the combination of these inherently chiral aromatic building blocks provides a novel access to a wide variety of conformationally ordered synthetic oligomers with diverse and dazzling structural architectures distinct from those classically observed.     

Conformationally Programmable Chiral Foldamers with Compact and Extended Domains Controlled by Monomer Structure

Foldamers are an important class of abiotic macromolecules, with potential therapeutic applications in the disruption of protein–protein interactions. The majority adopt a single conformational motif such as a helix. A class of foldamer is now introduced where the choice of heterocycle within each monomer, coupled with a strong conformation‐determining dipole repulsion effect, allows both helical and extended conformations to be selected. Combining these monomers into hetero‐oligomers enables highly controlled exploration of conformational space and projection of side‐chains along multiple vectors. The foldamers were rapidly constructed via an iterative deprotection‐cross‐coupling sequence, and their solid‐ and solution‐phase conformations were analysed by X‐ray crystallography and NMR and CD spectroscopy. These molecules may find applications in protein surface recognition where the interface does not involve canonical peptide secondary structures.     

Expanding the structural repertoire of β/α Ant-Pro (anthranilic acid-proline) oligomers into γ/α 2-Amb-Pro (2-aminomethyl benzoic acid-proline) oligomers

In this article, we report a novel class of heterogeneous synthetic oligomers featuring the conformationally constrained amino acid residues – 2-aminomethyl benzoic acid (2-Amb) and proline (Pro) in repeating sequences. Oligomers as large as hexadecamers featuring the conformationally restricted γ/α 2-Amb-Pro motif have been assembled using solution-phase Boc strategy, following multi-step synthetic sequences starting from the commercially available O-toluic acid. EDC-mediated peptide coupling has been found to be optimum for the assembly of the relatively non-polar oligomers, which could be readily purified by the standard column chromatographic purification procedures. This study offers considerable prospects of expanding the structural repertoire of β/α Ant-Pro motif, which has been described earlier to assume right-handed helical architecture displaying robust nine-membered-ring closed network of hydrogen-bonding interactions, into γ/α 2-Amb-Pro motif.     

Shape‐Persistent Aromatic Amide Oligomers: New Tools for Supramolecular Chemistry

With an increasing number of folding and helical structures available, chemists have begun to pay greater attention to the functions of this family of structurally unique oligomers. Hydrogen‐bonding‐mediated aromatic oligoamide foldamers have the features of good structural predictability, synthetic facility, and structural modification, which make them very promising as scaffolds or platforms for supramolecular chemistry. Recent advances in the applications of this class of shape‐persistent oligomers in the promoted synthesis of macrocycles, design of new nonring receptors, supramolecular self‐assembly, molecular encapsulation, and reaction acceleration, are highlighted in this Focus Review.     

Architecturally diverse nanostructured foldamers reveal insightful photoinduced single-molecule dynamics

Single molecule fluorescence spectroscopy has been used to probe architecturally diverse and unique model oligomers containing exactly two or four perylene tetracarboxylic diimide (PTDI) units: linear foldamers lin2 and lin4, monocyclic complement cyc2, and concatenated foldable rings cat4. Linear, cyclic, and concatenated foldamers reveal that photoabsorption and excitation induces unfolding and refolding, generating colorful spectral switching from one spectral type to another. Foldamer architectures dictate the unfolding and refolding processes, and hence the spectral dynamics. As a result, linear tetramer exhibits active frame-to-frame spectral switching accompanying dramatic changes in colors, but a concatenated tetramer displays a multicolored composite spectrum with little or no spectral switching. Excited state dynamics causes spectral switching: an electronically decoupled PTDI monomer emits green fluorescence while electronically coupled PTDI pi-stacks emit red fluorescence, with longer pi-stacks emitting redder fluorescence. A key question we address is the excited-state delocalization length, or the exciton coherence length, in the pi-stacks, which has been proven difficult to measure directly. Using foldamers having controlled sequences, structures, and well-defined length and chromophore numbers, we have mapped out the exciton coherence length in pi-stacks. Single molecule fluorescence studies on chromophoric foldamers reveal that the maximum domain length is delocalized across just four pi-stacked PTDI dyes and no new pure color can be found for oligomers beyond the tetramer. Therefore, the range of fluorescent colors in pi-stacks is a function of the number of chromophores only up to the tetramer.     

Hydrogen-bonding-induced oligoanthranilamide foldamers. Synthesis, characterization, and complexation for aliphatic ammonium ions

The self-assembly of a novel series of intramolecular hydrogen bonding-driven foldamers have been described. Five linear aromatic amide oligomers 1-5, which bear two to six repeating benzoyl amide subunits, respectively, have been prepared by continuous amide-coupling reactions. The existence of three-centered hydrogen bonds in the oligomers and consequently, the folding conformation of the oligomers in the solid state and solution have been proved by the X-ray analysis (for 2) and the ¹H NMR and IR experiments. Molecular modeling reveals a planar and rigid conformation for the oligomers and a cavity of 0.86 nm in diameter for 6-mer 5. Fluorescent and ¹H NMR experiments have demonstrated that the new aromatic oligo-amide foldamers can bind primary and secondary alkyl ammonium ions in chloroform and the associated binding constants have been determined. It is revealed that 5-mer 4 exhibits the largest binding ability. A face-to-face binding mode has been proposed for the complexes.     

阴离子协同组装折叠体

折叠体研究的目的是设计、合成和表征具有折叠结构的人工合成寡聚物,这些折叠体的折叠结构和自然界中的生物大分子如蛋白质的结构相似但不雷同。折叠体的研究发展为分子识别特别是阴离子识别提供了一个简单而非常有效的工具。本综述将主要介绍近几年国内外关于阴离子协同组装的折叠体的研究进展,探讨了折叠体和阴离子的相互作用规律。     

Aromatic oligomers that form hetero duplexes in aqueous solution

The electron-deficient 1,4,5,8-naphthalenetetracarboxylic diimide (Ndi) and electron-rich 1,5-dialkoxynaphthalene (Dan) have been shown to complex strongly with each other in water due to the hydrophobic effect as modulated through the electrostatic complementarity of the stacked dimer. Previously, oligomers of alternating Ndi and Dan units, termed aedamers, were the first foldamers to employ intramolecular aromatic stacking to effect the formation of secondary structure of nonnatural chains in aqueous solution. Described here is the use of this aromatic-aromatic (or pi-pi) interaction, this time in an intermolecular format, to demonstrate the self-assembly of stable hetero duplexes from a set of molecular strands (1a-4a) and (1b-4b) incorporating Ndi and Dan units, respectively. A 1-to-1 binding stoichiometry was determined from NMR and isothermal titration calorimetry (ITC) investigations, and these experiments indicated that association is enthalpically favored with the tetra-Ndi (4a) and tetra-Dan (4b) strands forming hetero duplexes (4a:4b) with a stability constant of 350 000 M-1 at T = 318 K. Polyacrylamide gel electrophoresis (PAGE) also illustrated the strong interaction between 4a and 4b and support a 1-to-1 binding mode even when one component is in slight excess. Overall, this system is the first to utilize complementary aromatic units to drive discrete self-assembly in aqueous solution. This new approach for designing assemblies is encouraging for future development of duplex systems with highly programmable modes of binding in solution or on surfaces.     

De Novo Left‐Handed Synthetic Peptidomimetic Foldamers

The development of peptidomimetic helical foldamers with a wide repertoire of functions is of significant interest. Herein, we report the X‐ray crystal structures of a series of homogeneous l ‐sulfono‐γ‐AA foldamers and elucidate their folding conformation at the atomic level. Single‐crystal X‐ray crystallography revealed that this class of oligomers fold into unprecedented dragon‐boat‐shaped and unexpected left‐handed helices, which are stabilized by the 14‐hydrogen‐bonding pattern present in all sequences. These l ‐sulfono‐γ‐AApeptides have a helical pitch of 5.1 Å and exactly four side chains per turn, and the side chains lie perfectly on top of each other along the helical axis. 2D NMR spectroscopy, computational simulations, and CD studies support the folding conformation in solution. Our results provide a structural basis at the atomic level for the design of novel biomimetics with a precise arrangement of functional groups in three dimensions.     

Solid phase synthesis of aromatic oligoamides: application to helical water-soluble foldamers

Synthetic helical aromatic amide foldamers and in particular those based on quinolines have recently attracted much interest due to their capacity to adopt bioinspired folded conformations that are highly stable and predictable. Additionally, the introduction of water-solubilizing side chains has allowed to evidence promising biological activities. It has also created the need for methods that may allow the parallel synthesis and screening of oligomers. Here, we describe the application of solid phase synthesis to speed up oligomer preparation and allow the introduction of various side chains. The synthesis of quinoline-based monomers bearing protected side chains is described along with conditions for activation, coupling, and deprotection on solid phase, followed by resin cleavage, side-chain deprotection, and HPLC purification. Oligomers having up to 8 units were thus synthesized. We found that solid phase synthesis is notably improved upon reducing resin loading and by applying microwave irradiation. We also demonstrate that the introduction of monomers bearing benzylic amines such as 6-aminomethyl-2-pyridinecarboxylic acid within the sequences of oligoquinolines make it possible to achieve couplings using a standard peptide coupling agent and constitute an interesting alternative to the use of acid chloride activation required by quinoline residues. The synthesis of a tetradecameric sequence was thus smoothly carried out. NMR solution structural studies show that these alternate aminomethyl-pyridine residues do not perturb the canonical helix folding of quinoline monomers in protic solvents, contrary to what was previously observed in nonprotic solvents.     

Conformational Adaptation of β-Peptide Foldamers for the Formation of Metal–Peptide Frameworks

Metal-coordinated frameworks derived from small peptidic ligands have received much attention thanks to peptides’ vast structural and functional diversity. Various peptides with partial conformational preferences have been used to build metal–peptide frameworks, however, the use of conformationally constrained β-peptide foldamers has not been explored yet. Herein we report the first metal-coordination-mediated assembly of β-peptide foldamers with 12-helical folding propensity. The coordination of Ag⁺ to the terminal pyridyl moieties afforded a set of metal–peptide frameworks with unique entangled topologies. Interestingly, formation of the network structures was accompanied by notable conformational distortions of the foldamer ligands. As the first demonstration of new metal–peptide frameworks built from modular β-peptide foldamers, we anticipate that this work will be an important benchmark for further structural evolution and mechanistic investigation.     

α‐Peptide–Oligourea Chimeras: Stabilization of Short α‐Helices by Non‐Peptide Helical Foldamers

Short α‐peptides with less than 10 residues generally display a low propensity to nucleate stable helical conformations. While various strategies to stabilize peptide helices have been previously reported, the ability of non‐peptide helical foldamers to stabilize α‐helices when fused to short α‐peptide segments has not been investigated. Towards this end, structural investigations into a series of chimeric oligomers obtained by joining aliphatic oligoureas to the C‐ or N‐termini of α‐peptides are described. All chimeras were found to be fully helical, with as few as 2 (or 3) urea units sufficient to propagate an α‐helical conformation in the fused peptide segment. The remarkable compatibility of α‐peptides with oligoureas described here, along with the simplicity of the approach, highlights the potential of interfacing natural and non‐peptide backbones as a means to further control the behavior of α‐peptides.     

Backbone-rigidified oligo(m-phenylene ethynylenes)

Oligo(m-phenylene ethynylenes) (oligo(m-PE)) with backbones rigidified by intramolecular hydrogen bonds were found to fold into well-defined conformations. The localized intramolecular hydrogen bond involves a donor and an acceptor from two adjacent benzene rings, respectively, which enforces globally folded conformations on these oligomers. Oligomers with two to seven residues have been synthesized and characterized. The persistence of the intramolecular hydrogen bonds and the corresponding curved conformations were established by ab initio and molecular mechanics calculations, 1D and 2D (1)H NMR spectroscopy, and UV spectroscopy. Pentamer 5, hexamer 6, and heptamer 7 adopt well-defined helical conformations. Such a backbone-based conformational programming should lead to molecules whose conformations are resilient toward structural variation of the side groups. These m-PE oligomers have provided a new approach for achieving folded unnatural oligomers under conditions that are otherwise unfavorable for previously described, solvent-driven folding of m-PE foldamers. Stably folded structures based on the design principle described here can be developed and may find important applications.     

Z/E isomerism in Nα-Nα-disubstituted hydrazides and the amidoxy bond: application to the conformational analysis of pseudopeptides built of hydrazinoacids and α-aminoxyacids

We have investigated the Z/E isomerism of the hydrazide link (CO-NH-N) and amidoxy link (CO-NH-O). The study was first focused on small molecular models using NMR and X-ray diffraction. It allowed determination of simple NMR criterions to differentiate easily the Z and E forms, which were then applied to investigate the behavior of these links inside the corresponding oligomers. Our results concerning the hydrazide link corroborate pioneering work that had been done in the 1970s except in the case were it is located inside aza-β(3)-cyclopeptides, where the old empirical rules failed to predict the right geometry of the link. The geometrical preference of the amidoxy bond is also unambiguously established and differs clearly from recent theoretical calculations. Our findings help rationalize the close self-organization ability of aza-β(3)-peptides and α-aminoxypeptides, two recently described foldamers.