A lysine-based 2:1-[α/aza]-pseudopeptide series used as additives in polymeric membranes for CO2 capture: synthesis, structural studies, and application.

The current study presents for the first time the synthesis of a new 2:1-[α/aza]-pseudopeptide series possessing charged amino acids (i.e., lysine) and aims at studying the influences of chirality, backbone length, and the nature of the lysine side chains on the conformation of the 2:1-[α/aza]-oligomers in solution using NMR, FTIR spectroscopy and molecular dynamic calculations. The spectroscopic results emphasized the conservation of the ß-turn conformation adopted by the trimers regardless of the chirality which demonstrated a noticeable effect on the conformation of homochiral hexamer (8c) compared with the hetero-analogue (8d). The molecular dynamic calculations predicted that the chirality and the side chain of the lysine residues caused a little distortion from the classical ß-turn conformation in the case of short trimer sequences (7c and 7d), while the chirality and the backbone length exerted more distortion on the ß-turn adopted by the longer hexamer sequences (8c and 8d). The large disturbance in hexamers from classical ß-turn was attributed to increasing the flexibility and the possibility of molecules to adopt a more energetically favorable conformation stabilized by non-classical ß-turn intramolecular hydrogen bonds. Thus, alternating d- and l-lysine amino acids in the 2:1-[α/aza]-hexamer (8d) decreases the high steric hindrance between the lysine side chains, as in the homo analogue (8c), and the distortion is less recognized. Finally, short sequences of aza-pseudopeptides containing lysine residues improve CO2 separation when used as additives in Pebax® 1074 membranes. The best membrane performances were obtained with a pseudopeptidic dimer as an additive (6b'; deprotected lysine side chain), with an increase in both ideal selectivity α CO2/N2 (from 42.8 to 47.6) and CO2 permeability (from 132 to 148 Barrer) compared to the virgin Pebax® 1074 membrane.

Emerging low-molecular weight nucleopeptide-based hydrogels: state of the art, applications, challenges and perspectives.

Over the last twenty years, low-molecular weight gelators and, in particular, peptide-based hydrogels, have drawn great attention from scientists thanks to both their inherent advantages in terms of properties and their high modularity (e.g., number and nature of the amino acids). These supramolecular hydrogels originate from specific peptide self-assembly processes that can be driven, modulated and optimized via specific chemical modifications brought to the peptide sequence. Among them, the incorporation of nucleobases, another class of biomolecules well-known for their abilities to self-assemble, has recently appeared as a new promising and burgeoning approach to finely design supramolecular hydrogels. In this minireview, we would like to highlight the interest, high potential, applications and perspectives of these innovative and emerging low-molecular weight nucleopeptide-based hydrogels.

Co-assembly and multicomponent hydrogel formation upon mixing nucleobase-containing peptides.

Peptide-based hydrogels are physical gels formed through specific supramolecular self-assembling processes, leading to ordered nanostructures which constitute the water entrapping scaffold of the soft material. Thanks to the inherent properties of peptides, these hydrogels are highly considered in the biomedical domain and open new horizons in terms of application in advanced therapies and biotechnologies. The use of one, and only one, native peptide to formulate a gel is by far the most reported approach to design such materials, but suffers from several limitations, including in terms of mechanical properties. To improve peptide-based hydrogels interest and give rise to innovative properties, several strategies have been proposed in the recent years, and the development of multicomponent peptide-based hydrogels appears as a promising and relevant strategy. Indeed, mixing two or more compounds to develop new materials is a much-used approach that has proven its effectiveness in a wide variety of domains, including polymers, composites and alloys. While still limited to a handful of examples, we would like to report herein on the formulation and the comprehensive study of multicomponent hybrid DNA-nucleobase/peptide-based hydrogels using a multiscale approach based on a large panel of analytical techniques (i.e., rheometry, proton relaxometry, SAXS, electronic microscopy, infrared, circular dichroism, fluorescence, Thioflavin T assays). Among the six multicomponent systems studied, the results highlight the synergistic role of the presence of the two complementary DNA-nucleobases (i.e., adenine/thymine and guanine/cytosine) on the co-assembling process from structural (e.g., morphology of the nanoobjects) to physicochemical (e.g., kinetics of formation, fluorescence properties) and mechanical (e.g., stiffness, resistance to external stress) properties. All the data confirm the relevance of the multicomponent peptide-based approach in the design of innovative hydrogels and bring another brick in the wall of the understanding of these complex and promising systems.

Improving and fine-tuning the properties of peptide-based hydrogels via incorporation of peptide nucleic acids.

Peptide self-assemblies have attracted intense research interest over the last few decades thanks to their implications in key biological processes (e.g., amyloid formation) and their use in biotechnological and (bio)material fields. In particular, peptide-based hydrogels have been highly considered as high potential supramolecular materials in the biomedical domain and open new horizons in terms of applications. To further understand their self-assembly mechanisms and to optimize their properties, several strategies have been proposed with the modification of the constituting amino acid chains via, per se, the introduction of d-amino acids, halogenated amino acids, pseudopeptide bonds, or other chemical moieties. In this context, we report herein on the incorporation of DNA-nucleobases into their peptide nucleic acid (PNA) forms to develop a new series of hybrid nucleopeptides. Thus, depending on the nature of the nucleobase (i.e., thymine, cytosine, adenine or guanine), the physicochemical and mechanical properties of the resulting hydrogels can be significantly improved and fine-tuned with, for instance, drastic enhancements of both the gel stiffness (up to 70-fold) and the gel resistance to external stress (up to 40-fold), and the generation of both thermo-reversible and uncommon red-edge excitation shift (REES) properties. To decipher the actual role of each PNA moiety in the self-assembly processes, the induced modifications from the molecular to the macroscopic scales are studied thanks to the multiscale approach based on a large panel of analytical techniques (i.e., rheology, NMR relaxometry, TEM, thioflavin T assays, FTIR, CD, fluorescence, NMR chemical shift index). Thus, such a strategy provides new opportunities to adapt and fit hydrogel properties to the intended ones and pushes back the limits of supramolecular materials.

Cyclohexamer [-(d-Phe-azaPhe-Ala)2-]: good candidate to formulate supramolecular organogels.

Molecular self-assembly is a fascinating process which has become an area of great interest in supramolecular chemistry, as it leads in certain cases to molecular gels. Organogels formulated from low molecular weight compounds (LMWOGs) have attracted much interest in the past decades due to their applications as new soft materials. Herein, we report on the ability of the cyclic pseudopeptide cyclo-[-(d-Phe-azaPhe-Ala)2-] (2) to self-assemble in some aromatic solvents and to form organogels driven by non-covalent forces, mainly hydrogen bonding and π-stacking interactions. Comprehensive FTIR and NMR studies emphasized that this cyclic aza-peptide adopts a ß-turn conformation at low concentration in toluene, while an equilibrium between the monomeric states (intramolecular forces) and the supramolecular structures (intra- and intermolecular forces) is established at high concentration (gel state). Rheological investigations of the organogels highlight the dependence of their stiffness (up to ∼4 kPa) and sol/gel transition temperatures (up to 100 °C) as a function of the solvent and concentration of gelator used. The formulation of fibrous structures confirmed the phenomenon of self-assembly. Finally, we found that cyclo-[-(d-Phe-azaPhe-Ala)2-] is an effective organogelator for application in phase selective gelation (PSG) of organic solvents from aqueous/organic mixtures with recovery percents up to 96%.

(S)-ABOC: a rigid bicyclic ß-amino acid as turn inducer.

In order to investigate the ability of the (S)-aminobicyclo[2.2.2]octane-2-carboxylic acid 1 (H-(S)-ABOC-OH) to induce reverse turns into peptides, two model tripeptides, in which this bicyclic unit was incorporated into the second position, were synthesized and analyzed by FT-IR, CD, NMR, and X-ray studies.

A favorable, narrow, δ(h) Hansen-parameter domain for gelation of low-molecular-weight amino acid derivatives.

In recent years, the design of new low-molecular-weight gelators (LMWGs) has attracted considerable attention because of the interesting supramolecular architectures as well as industrial applications. In this context, the role of the organic solvent in determining the organogelation behavior is a central question. Herein we report the results of a systematic study of the organogelation behavior of amino acid derivatives in a wide range of solvents to establish a relationship between the nature of the solvent and the formation of the gel. We highlight that the majority of the gelified solvents are aromatic, except for carbon tetrachloride and tetrachloroethylene. In addition, different parameters related to the nature of the solvent were considered and their influence on the physical properties of gelation was evaluated. The hydrogen-bonding Hansen parameter (δ(h)) allows us to draw a narrow favorable δ(h) domain for gelation in the range of 0.2-1.4 (cal cm(-3))(1/2). Furthermore, a general increase of the Hildebrand parameter (δ) leads to the formation of poor gels (small gelation numbers, GNs) in aromatic solvents. Scanning electron microscopy (SEM) revealed that the gels prepared from (l)-phenylalanine and (l)-leucine derivatives in different solvents are composed of an entangled 3D fibrillar network, the diameter of which is only slightly influenced by the nature of the solvent.

Evidence of intercolumnar π-π stacking interactions in amino-acid-based low-molecular-weight organogels.

A comparative IR and NMR study of two low-molecular-weight organogels (LMWGs) based on aminoacid derivatives let us point out the hierarchy of the gelation assembly process. Different association states of corresponding organogelator molecules can be observed leading to the supramolecular organization of gel. A first hydrogen bond network of gelators leads to the formation of "head-to-tail" stacking-up, which can be assembled afterward one to the other by π-π stacking interactions. These small supramolecular aggregates (incipient precursor) are still visible in NMR spectra, and they represent, for example, 36% of the total amount of gelator in the case of the L-phenylalanine derivative (gelator 1) at 1 wt % in toluene. Finally, in the last step, the incipient precursor tends to form the expected 3D fibrillar network responsible for the gelation phenomenon. Temperature-dependent IR and NMR experiments allowed us to identify these different states clearly.

Imidazole and dimethyl aminopropyl-functionalized hyperbranched polymers for nucleic acid transfection.

In order to mimic the histidine binding motives of naturally occurring histones as DNA complexing proteins, hyperbranched poly(ethylene imine) and polyglycerol were functionalized with imidazole or 3-dimethylamino propyl groups. These new polycationic polymers were tested for interaction with dye-labelled oligonucleotide and DNA using UV and fluorescence spectroscopy and gel electrophoresis. Formation of stable complexes was observed above N/P ratios of 4 for unfunctionalized and 8 for functionalized PEIs. No stable complexes were formed with polyglycerol-based polyamines up to N/P 16. Cytotoxicity determined by MTT assay of all functionalized PEI polymers was found to be significantly lower than for unfunctionalized PEI. PG-based polymers showed no toxicity in the tested concentration range. Dynamic light scattering showed that only for PEI(21)-Imidaz polyplexes hydrodynamic diameters below 250 nm could be reached.The influence of functionalization and polymer type on transfection efficiency was evaluated in L929, NIH/3T3 and HeLa cells. Only imidazole-functionalized PEIs reached similar transfection efficiencies as unfunctionalized PEIs, while 3-dimethylamino propyl modification resulted in lower transfection efficiencies. We also demonstrated that the polymer plays an important role for transfection properties since, regardless of the modifications of polyglycerol, only low transfection efficiencies were observed at functionalization levels below 50%.

Tuning organogels and mesophases with phenanthroline ligands and their copper complexes by inter- to intramolecular hydrogen bonds.

A novel family of highly functionalized molecules consisting of a central 4-methyl-3,5-diacylaminobenzene platform linked in close proximity to the methyl group by two lateral aromatic rings each equipped with two long alkoxy chains has been rationally designed. The presence of amide tethers and a chelating phenanthroline fragment connected via an ester dipole formed a new class of gelating reagents and mesomorphic materials. A few of these compounds have the tendency to form macromolecule-like aggregates through noncovalent interactions in hydrocarbon solvents and were found to exhibit thermotropic cubic mesophases. In light of the X-ray molecular structure of the methoxy ligand, an infinite network maintained by intermolecular hydrogen bonds as well as by pi-pi stacking of the phenyl subunits was evidenced. FT-IR studies confirm that the common driving force for aggregation in the organogels and microsegregation in the mesophase is the occurrence of a tight intermolecular H-bonded network that does not persist in diluted solution. This situation is switched when the ligands are interlocked by a copper(I) cation. A strong intramolecular H-bond confirmed by X-ray diffraction of a single crystal for the methoxy case provides very stable complexes but inhibits the gelation of the solvents. Heating the complexes bearing long paraffin chains (n = 12 and 16) in the dried state leads to a self-organization into a columnar liquid-crystalline phase in which the columns are arranged along a 2D oblique symmetry as deduced from powder XRD experiments. In this case, the complexes with the appended counteranions self-assemble in a specific way to form columns. A striking observation is that the intramolecular hydrogen bond persists in the mesophase as it does in solution without any evidence of an extended network. As far as we are aware, these ligands and complexes are rare examples in which organogelation and thermotropic mesomorphic behavior could be observed in parallel with molecules bearing a chelating platform. Due to the synthetic availability of the 4-methyl-3,5-diacylaminobenzene core and the simplicity by which the chelating platforms can be graphed, this methodology represents a practical alternative to the production of functionalized organogelators and mesomorphic materials.

A convenient protocol for the synthesis of ligands from a 4-methyl-3,5-diacylaminophenyl platform.

The synthesis of stable and highly organized phenanthroline, terpyridine, and pyridino-oxazoline ligands bearing one or two 4-methyl-3,5-diacylaminophenyl modules equipped with two lateral dialkoxyphenyl groups has been performed using EDC.HCl and DMAP reagents in the final coupling reaction. Evidently, in the final ligands and in the solid state intermolecular hydrogen bonding maintains the coherence of the tridimensional structure as clearly evidenced by FT-IR and X-ray diffraction spectroscopy in the cases of the methoxy ligands. The supramolecular packing is also maintained by additional pi-pi stacking interactions.

Mesomorphic phenanthroline derivatives: novel architectures based on hydrogen bonding.

Strong hydrogen bonding has been observed in mesomorphic phenanthroline compounds engineered from diacylaminobenzene platforms: a columnar organization is found in the free ligands (n = 12 or 16) whereas a smectic arrangement is evidenced in a palladium complex (n = 16).