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Hybrids of short oligourea foldamers with residues of α, β and γ-amino acids esters at the C-terminus were obtained and subjected to a reaction with LiOH. There are two possible transformations under such conditions, one of which is ester hydrolysis and the formation of a carboxylic group and the other is the cyclization reaction after abstraction of a proton from urea by a base. We have investigated this reaction with difference C-terminal residue structures, as well as under different work-up conditions, especially for oligourea hybrids with α-amino acid esters. For these compounds, an oligourea–hydantoin combination is the product of cyclization. The stability of the hydantoin ring under alkaline conditions has been alsotested. Furthermore, this work reports data related to the structure of C-terminal-modified oligourea foldamers in solution and, for one compound, in the solid state. Helical folding is preserved both for cyclized and linear modifications, with oligourea–acid hybrids appearing to be more conformationally stable, as they are stabilized by an additional intramolecular hydrogen bond in comparison to cyclic derivatives.

International audience; Amphipathic water-soluble helices formed from synthetic peptides or foldamers are promising building blocks for the creation of self-assembled architectures with non-natural shapes and functions. While rationally designed artificial quaternary structures such as helix bundles have been shown to contain preformed cavities suitable for guest binding, there are no examples of adaptive binding of guest molecules by such assemblies in aqueous conditions. We have previously reported a foldamer 6-helix bundle that contains an internal nonpolar cavity able to bind primary alcohols as guest molecules. Here, we show that this 6-helix bundle can also interact with larger, more complex guests such as n-alkyl glycosides. X-ray diffraction analysis of co-crystals using a diverse set of guests together with solution and gas-phase studies reveals an adaptive binding mode whereby the apo form of the 6-helix bundle undergoes substantial conformational change to accommodate the hydrocarbon chain in a manner reminiscent of glycolipid transfer proteins in which the cavity forms upon lipid uptake. The dynamic nature of the self-assembling and molecular recognition processes reported here marks a step forward in the design of functional proteomimetic molecular assemblies.

Oligourea foldamers fold into 2.5-helices. Most of the known modifications of the backbone, such as NH or CO group substitutions or incorporations of non-canonical residues, do not change the conformational properties of the resulting oligourea oligomers. In this study, we examined the structural influence of the methyl group, substituting NH protons in one or two residues at the N-terminus of the foldamer. Such N-methylated oligoureas appear to be helically folded with helix parameters determined from the crystal structure being almost the same as for non-methylated oligomers. Solution studies (CD, NMR) reveal that the backbone with N-Me urea groups is more flexible, but the urea group is still predominantly in trans,trans conformation. N-Methylation does not change the structural properties of oligourea foldamers, and thus may be a useful modification for modulating the strength of hydrogen bonds and intermolecular interactions.

We have designed and synthesized two α-helicomimetic foldamers composed of six urea residues with terminal ferrocene and cysteamine moieties. The direction of the net dipole moment in these two com...

Neuropilin-1 (NRP-1), the major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2), may also independently act with VEGF-A165 to stimulate tumour growth and metastasis. Therefore, there is great interest in compounds that can block VEGF-A165/NRP-1 interaction. Peptidomimetic type inhibitors represent a promising strategy in the treatment of NRP-1-related disorders. Here, we present the synthesis, affinity, enzymatic stability, molecular modeling and in vitro binding evaluation of the branched urea&ndash, peptide hybrids, based on our previously reported Lys(hArg)-Dab-Oic-Arg active sequence, where the Lys(hArg) branching has been modified by introducing urea units to replace the peptide bond at various positions. One of the resulting hybrids increased the affinity of the compound for NRP-1 more than 10-fold, while simultaneously improving resistance for proteolytic stability in serum. In addition, ligand binding to NRP-1 induced rapid protein stock exocytotic trafficking to the plasma membrane in breast cancer cells. Examined properties characterize this compound as a good candidate for further development of VEGF165/NRP-1 inhibitors.

We report here an oligourea foldamer able to self-assemble in aqueous conditions into helix bundles of multiple stoichiometries. Importantly, we report crystal structures of several of these stoichiometries, providing a series of high-resolutions snap-shots of the structural polymorphism of this foldamer and uncovering a novel self-assembly.

α-Helicomimetic oligoureas are a class of compounds with a broad spectrum of applications, yet their use in materials science remains still unexplored. In this work, we have synthesized three oligomers composed of 8–12 residues and studied their electron transport characteristic. We have found that the conductance of oligoureas depends on the length of the molecule. The distance dependence yields a low value of the decay constant, which indicates that the dominant mechanism is hopping. Moreover, we describe here an entirely new property of oligoureas, that is, directional dependence of electron transport. The latter is manifested on current–voltage characteristic as current rectification. The highest rectification ratio observed was ≈12, which is around 3 times greater than that observed for helical peptides of similar length. This effect demonstrates that carefully designed oligomers with a well-defined secondary structure (e.g., oligourea foldamers) may be considered as potential candidates for use in n...

We have synthesized an oligourea foldamer containing seven urea residues, with a Cys-like residue introduced near the N-terminus of the helix. This enabled the immobilization of the molecules on gold electrode using gold-sulfur chemistry. Molecular layer was characterized by electrochemical and spectroelectrochemical methods. Electrochemical measurements confirmed the formation of a dielectric layer on the electrode surface and the determined potential of zero free charge proved that the molecules are adsorbed with the positive pole of the dipole pointing to the electrode surface. The measurements with the use of in situ surface-enhanced infrared absorption spectroscopy provided insight into the dynamics of molecules under the influence of the electric field. Namely, helical oligourea molecules undergo reversible potential-induced changes in the orientation of the molecules. Our results show that molecular layers of oligourea helical foldamers can be used as building blocks for assembly of stimuli-responsive molecular layers serving as molecular lifters triggered by electric field.

NRP-1 is an important co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2). Many reports suggested that NRP-1 might also serve as a separate receptor for VEGF-A165 causing stimulation of tumour growth and metastasis. Therefore, compounds interfering with VEGF-A165/NRP-1 complex triggered interest in the design of new molecules, including peptides, as anti-angiogenic and anti-tumour drugs. Here, we report the synthesis, affinity and stability evaluation of the urea-peptide hybrids, based on general Lys(hArg)-AA2-AA3-Arg sequence, where hArg residue was substituted by Arg urea unit. Such substitution does not substantially affected affinity of compounds for NRP-1 but significantly increased their proteolytic stability in plasma.

Non-natural synthetic oligomers that adopt well-defined secondary structures (i.e., foldamers) represent appealing components for the fabrication of bioinspired self-assembled architectures at the nanometer scale. Recently, peptidomimetic N,N'-linked oligourea helices have been designed de novo with the ability to fold into discrete helix bundles in aqueous conditions. In order to gain better insight into the determinants of oligourea helix bundle formation, we have investigated the sequence-to-structure relationship of an 11-mer oligourea previously shown to assemble into a six-helix bundle. Using circular dichroism, NMR spectroscopy, native mass-spectrometry and X-ray crystallography, we studied how bundle formation was affected by systematic replacement of the hydrophobic surface of the oligourea helix with either polar or different hydrophobic side chains. The molecular information gathered here has revealed several key requirements for foldamer bundle formation in aqueous conditions, and provides valuable insight toward the development of foldamer quaternary assemblies with improved (bio)physical properties and divergent topologies.

International audience; The synthesis of hybrid urea-based foldamers containing isosteric guanidinium linkages at selected positions in the sequence is described. We used a postelongation approach whereby the guanidinium moiety is introduced by direct transformation of a parent oligo(urea/thiourea) foldamer precursor. The method involves activation of the thiourea by treatment with methyl iodide and subsequent reaction with amines. To avoid undesired cyclization with the preceding urea moiety, resulting in heterocyclic guanidinium formation in the main chain, the urea unit preceding the thiourea unit in the sequence was replaced by an isoatomic and isostructural gamma-amino acid. The approach was extended to solid-phase techniques to accelerate the synthesis of longer and more functionalized sequences. Under optimized conditions, an octamer hybrid oligomer incorporating a central guanidinium linkage was obtained in good overall yield and purity. This work also reports data related to the structural consequences of urea by guanidinium replacements in solution and reveals that helical folding is substantially reduced in oligomers containing a guanidinium group.

The Pictet-Spengler (PS) cyclizations of β(3)-hTrp derivatives as arylethylamine substrates were performed with L-α-amino and D-α-amino aldehydes as carbonyl components. During the PS reaction, a new stereogenic center was created, and the mixture of cis/trans 1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines was obtained. The ratio of cis/trans diastereomers depends on the stereogenic centre of used amino aldehyde and the size of substituents. It was confirmed by 1H and 2D NMR (ROESY) spectra. The conformations of cyclic products were studied by 2D NMR ROESY spectra. Products of the PS condensation after removal of protecting group(s) can be incorporated into a peptide chain as tryptophan mimetics with the possibility of the β-turn induction.

The design and construction of biomimetic self-assembling systems is a challenging yet potentially highly rewarding endeavour that contributes to the development of new biomaterials, catalysts, drug-delivery systems and tools for the manipulation of biological processes. Significant progress has been achieved by engineering self-assembling DNA-, protein- and peptide-based building units. However, the design of entirely new, completely non-natural folded architectures that resemble biopolymers ('foldamers') and have the ability to self-assemble into atomically precise nanostructures in aqueous conditions has proved exceptionally challenging. Here we report the modular design, formation and structural elucidation at the atomic level of a series of diverse quaternary arrangements formed by the self-assembly of short amphiphilic α-helicomimetic foldamers that bear proteinaceous side chains. We show that the final quaternary assembly can be controlled at the sequence level, which permits the programmed formation of either discrete helical bundles that contain isolated cavities or pH-responsive water-filled channels with controllable pore diameters.

Cyclic peptides containing redox-stable thioether bridges might provide a useful alternative to disulfide-bridged bioactive peptides. We report the effect of replacing the disulfide bridge with a lanthionine linkage in a 16-mer cyclic peptide that binds to death receptor 5 (DR5, TRAIL-R2). Upon covalent oligomerisation, the disulfide-bridged peptide has previously shown similar behaviour to that of TNF-related apoptosis inducing ligand (TRAIL), by selectively triggering the DR5 cell death pathway. The structural and biological properties of the DR5-binding peptide and its desulfurised analogue were compared. Surface plasmon resonance (SPR) data suggest that these peptides bind DR5 with comparable affinities. The same holds true for dimeric versions of these peptides: the thioether is able to induce DR5-mediated apoptosis of BJAB lymphoma and tumorigenic BJELR cells, albeit to a slightly lower extent compared to its disulfide homologue. NMR analysis revealed subtle variation in the conformations of the two peptides and suggests that the thioether peptide is slightly less folded than its disulfide homologue. These observations could account for the different capability of the two dimers to cluster DR5 receptors on the cell surface and to trigger apoptosis. Nevertheless, our results suggest that the thioether peptide is a potential candidate for evaluation in animal models.

Artificial synthetic molecules able to adopt well-defined stable secondary structures comparable to those found in nature ("foldamers") have considerable potential for use in a range of applications such as biomaterials, biorecognition, nanomachines and as therapeutic agents. The development of foldamers with the ability to bind and encapsulate "guest" molecules is of particular interest; as such an ability is a key step toward the development of artificial sensors, receptors and drug-delivery vectors. Although significant progress has been reported within this context, foldamer capsules reported thus far are largely restricted to organic solvent systems, and it is likely that the move to aqueous conditions will prove challenging. Toward this end, we report here structural studies into the ability of a recently reported water-soluble self-assembled foldamer helix bundle to encapsulate simple guest molecules within an internal cavity. Seven high-resolution aqueous crystal structures are reported, accompanied by molecular dynamics and high-field NMR solution data, showing for the first time that encapsulation of guests by a complex self-assembled foldamer in aqueous conditions is possible. The findings also provide ample insight for the future functional development of this system.

The Pictet–Spengler (PS) reaction was performed with various types of substrates: H-Trp-OMe and dipeptides with N-terminal Trp as arylethylamine components and Z-protected amino aldehydes and peptidoaldehydes as carbonyl components. We found that the C-terminal part of Trp derivatives did not have any influence on the stereoselectivity of the reaction and the results are the same for simple esters of Trp and dipeptides. On the contrary, the selectivity of the PS reaction with peptidoaldehydes with L configuration of the C-terminus residue is totally different from that obtained with simple L-amino aldehydes. It allows us to obtain cis stereoisomers, which cannot be isolated from the reaction with amino aldehydes. But the utility of the peptidoaldehydes as substrates for the PS reaction is reduced by the side formation of enamides which decrease the yield of cyclization. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

Common surfactants promote the crystallisation of a series of water-soluble oligourea foldamers which had previously proven resistant to crystallisation efforts., X-ray crystallography has played a major role in the advancement of foldamer research, however, obtaining well-formed single crystals of suitable quality for structure determination by X-ray diffraction methods is often rather challenging. Towards this end, we report here the ability of common surfactants to promote the crystallisation of a series of water-soluble oligourea foldamers which had previously proven highly resistant to crystallisation. Four high-resolution crystal structures are reported, suggesting certain surfactants could be potentially useful tools for the crystallisation of intractable water-soluble foldamers (or peptides).

We report here the efficient in situ iodination of tyrosine-type side-chains located within a foldamer helix bundle, permitting structure determination using single-wavelength anomalous diffraction (SAD) methods. We suggest that this simple method may be of use to those engaged in structural foldamer research as a potential solution to the phase problem.

A practical and efficient microwave-assisted solid-phase method for the synthesis of N,N'-linked oligoureas and related amide/urea hybrid oligomers, featuring the use of succinimidyl (2-azido-2-substituted ethyl) carbamate monomers, is reported. The rate enhancement of urea formation under microwave irradiation combined with the mild conditions of the phosphine-based azide reduction makes this approach very effective for routine synthesis of oligoureas and possibly for library production.

The Pictet–Spengler reaction with N-protected α-amino aldehydes was found to be very sensitive to reaction conditions. The outcome of the reaction can be controlled mainly by choice of solvent. Tetrahydro-β-carbolines were obtained in apolar solvents, while in polar media octahydro-bipyrroloindoles were the main compounds. Temperature, amount of acid and reaction time also influenced the final results of the PS reaction. Depending on conditions, products with opposite configuration of stereogenic centre, descended from amino aldehydes, were formed as byproducts.

Working with thiols is associated with the risk of unwanted oxidation reactions, which includes the formation of disulfides. Here, the use of short peptidomimetic oligoureas as a model system to study the influence of reaction conditions on the thiol oxidation process is described. The formation of disulfide bond is usually performed in aqueous solutions; in this study, it was shown that the oxidation reaction occurs also in organic medium. It was discovered that the rate of the oxidation reaction strongly depends on the type of solvent, which is the consequence of the change of the oxidant (air or DMSO), the temperature, and the presence (or absence) of base. The details reported here may help those working with thiols to find suitable conditions to control the oxidation behaviour in organic solvents, ensuring that ─SH groups either remain intact or form disulfide bonds as desired.

The Pictet-Spengler reaction is known as a useful tool for the synthesis of constrained analogs of tryptophan. Herein, we present the further cyclization of 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid methyl esters with 1-(1'-aminoalkyl) side chain. These transformations lead to heterocyclic structures which can find useful applications in medicinal chemistry as peptide mimetics.

The synthesis of tryptophan analogs is reported in which the conformation has been constrained by formation of a seven-membered lactam. Boc-protected 2′-formyl tryptophan was obtained by SeO2 oxidation of Boc-tetrahydro-β-carboline-3-carboxylic acid. Reductive amination was performed with a variety of amines and amino acid esters using sodium cyanoborohydride, followed by ring closure to the target compounds. The constrained Trp derivative has been incorporated into the endomorphin-1 opioid peptide sequence to probe the bioactive conformation.

The Pictet-Spengler (PS) cyclizations of β(3)-hTrp derivatives as arylethylamine substrates were performed with L-α-amino and D-α-amino aldehydes as carbonyl components. During the PS reaction, a new stereogenic center was created, and the mixture of cis/trans 1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines was obtained. The ratio of cis/trans diastereomers depends on the stereogenic centre of used amino aldehyde and the size of substituents. It was confirmed by 1H and 2D NMR (ROESY) spectra. The conformations of cyclic products were studied by 2D NMR ROESY spectra. Products of the PS condensation after removal of protecting group(s) can be incorporated into a peptide chain as tryptophan mimetics with the possibility of the β-turn induction.

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.

This article presents kinetic studies of cross interaction ofβ-amyloid peptide and prion protein fragments. Synthesesof three peptides (β25–35, β22–35 and PrP 109–126) were performed. Those peptides were used for aggregation studies in PBS and TRIS buffers using HPLC with DAD detector. Comparison of aggregation of peptides alone and incombination with other fragments was investigated. In all cases aggregation was faster in PBS than in TRIS solution. Obtained results suggest that β-amyloid peptide and prion protein may interact to form macromolecular complexes with different ability for aggregation.

The Pictet-Spengler (PS) reaction was performed with various types of substrates: H-Trp-OMe and dipeptides with N-terminal Trp as arylethylamine components and Z-protected amino aldehydes and peptidoaldehydes as carbonyl components. We found that the C-terminal part of Trp derivatives did not have any influence on the stereoselectivity of the reaction and the results are the same for simple esters of Trp and dipeptides. On the contrary, the selectivity of the PS reaction with peptidoaldehydes with L configuration of the C-terminus residue is totally different from that obtained with simple L-amino aldehydes. It allows us to obtain cis stereoisomers, which cannot be isolated from the reaction with amino aldehydes. But the utility of the peptidoaldehydes as substrates for the PS reaction is reduced by the side formation of enamides which decrease the yield of cyclization.

The synthesis of biologically active heterocyclic scaffolds is one of the significant challenges of modern synthetic chemistry. The Pictet-Spengler (PS) reaction, known for approximately a century, remains a particularly popular cyclization method. This review describes recent applications of the PS reaction in the total synthesis of alkaloids and biologically active analogs of tetrahydroisoquinoline and tetrahydro-β-carboline. The utility of PS cyclization in the synthesis of a range of heterocyclic scaffolds is also described.

The synthesis of biologically active heterocyclic scaffolds is one of the significant challenges of modern synthetic chemistry. The Pictet-Spengler (PS) reaction, known for approximately a century, remains a particularly popular cyclization method. This review describes recent applications of the PS reaction in the total synthesis of alkaloids and biologically active analogs of tetrahydroisoquinoline and tetrahydro-β-carboline. The utility of PS cyclization in the synthesis of a range of heterocyclic scaffolds is also described.

Ampholytic polymer gels based on N-isopropylacrylamide (NIPA) and natural amino acid L-lysine were prepared by free radical polymerization in aqueous solutions. To make amino acids attachable to the polymer chain, the acrylic group was added to the epsilon-amino group of lysine to obtain N-epsilon-acrylic-lysine (Z). Finally, a new temperature- and pH-sensitive (NIPA-Z) hydrogel was obtained. The presence of amino and carboxylic groups of amino acids gave us a possibility to control the amount and sign of the excessive charge on the polymeric network with respect to pH. The swelling behavior of the NIPA-Z hydrogels with respect to the amount of Z (0-4%), temperature, and pH was investigated. Temperature and pH were changed in the ranges of 20-50 degrees C and 2-12, respectively. To eliminate the influence of ionic strength on the swelling behavior, this parameter was kept constant in all experiments. It was found that the pH dependence of the degree of swelling for the NIPA-Z gels, measured at constant temperature, exhibits a minimum. Such a minimum was seen for the ampholyte networks with independent acidic and basic groups attached to the polymer chains. For the NIPA-Z gels, the minimum was wide, and the pH range over which it was spread corresponded well to the pH distribution of the zwitterions. The way the gel volume changed with an increase in temperature depends on the amino acid amount. It is initially discontinuous and turns to the continuous one for the higher percentage of amino acid. The temperature dependence of the swelling process obtained for different pH values clearly shows that for the pH region where the zwitterions dominate, the polymer networks collapse more efficiently.