An alternative approach to create N -substituted cyclic dipeptides

International audienceN-Modified peptide backbones are promising peptidomimetics which offer several advantages in terms of improved biological activity and stability. They further allow the development of novel functional materials. However, the synthesis of N-substituted peptides is very challenging with the existing methods, particularly the synthesis of peptides with larger N-substituents. In this work, we are introducing a new method to create N-polyether substituted cyclic dipeptides via anionic ring-opening polymerization (AROP). Four different cyclic dipeptides with different hydrophobic functional groups were selected to create N-substituted cyclic dipeptides. Backbone amides –NH– were deprotonated with phosphazene bases to form nucleophilic initiators. Furthermore, the effect of different phosphazene bases (tBuP4 and tBuP2) and of the addition of a Lewis acid (i-Bu3Al) was studied in detail towards creating N-polyether-cyclic dipeptides bearing either hydrophobic poly(butylene oxide) chains, or hydrophilic linear polyglycidol chains, thanks to the polymerization of 1,2-epoxybutane and the polymerization followed by the deprotection of t-butyl glycidyl ether monomers, respectively. Moreover, we have demonstrated the possibility of avoiding the isomerization of cyclic dipeptides during the synthesis of N-substituted analogues depending on the synthetic approach

Synthesis of tetraarm star block copolymer based on polytetrahydrofuran and poly(2-methyl-2-oxazoline) for gene delivery applications

International audienceNew star shaped block copolymers were synthesized according to a core first strategy, with a hydrophobic polytetrahydrofuran (PTHF) central block and a poly(2-methyl-2-oxazoline) (PMeOx) external block. First, the cationic polymerization of THF was initiated from a tetrafunctional triflate ester synthesized in situ. The chain ends were functionalized by quenching the polymerization with an excess of MeOx, that allowed for the MeOx polymerization under microwave in a subsequent step. Demonstration of the expected structures was carried out at each step of the polymerization. The controlled molar mass of the star copolymers was kept below 5000 g mol À1 in order to mimick the structure of the efficient poloxamines for gene transfer applications. Formulations containing various concentrations of star block copolymers were intramuscularly injected in mice. Efficient gene transfer was measured at formulations with very low concentration of copolymer compared to reference standard containing Lutrol Ò

β-Cyclodextrin-Based Star Amphiphilic Copolymers: Synthesis, Characterization, and Evaluation as Artificial Channels

International audience14‐arm amphiphilic star copolymers are synthesized according to different strategies. First, the anionic ring polymerization of 1,2‐butylene oxide (BO) initiated by per(2‐O‐methyl‐3,6‐di‐O‐(3‐hydroxypropyl))‐β‐CD (β‐CD’OH14) and catalyzed by t‐BuP4 in DMF is investigated. Analyses by NMR and SEC show the well‐defined structure of the star β‐CD’‐PBO14. To obtain a 14‐arm poly(butylene oxide‐b‐ethylene oxide) star, a Huisgen cycloaddition between an α‐methoxy‐ω‐azidopoly(ethylene oxide) and the β‐CD’‐PBO14,whose end‐chains are beforehand alkyne‐functionalized, is performed. In parallel, 14‐arm star copolymers composed of butylene oxide‐b‐glycidol arms are successfully synthesized by the anionic polymerization of ethoxyethylglycidyl ether (EEGE) initiated by β‐CD’‐PBO14 with t‐BuP4. The deprotection of EEGE units is then performed to provide the polyglycidol blocks. These amphiphilic star polymers are evaluated as artificial channels in lipid bilayers. The effect of changing a PEO block by a polyglycidol block on the insertion properties of these artificial channels is discussed

Tuneable thermal properties of PTHF-based copolymers by incorporation of epoxide units

International audienceIn order to decrease the crystallinity of polytetrahydrofuran (PTHF), statistical copolymerizations with 1,2butylene oxide (BO) and 3,3-dimethyl-1,2-butylene oxide (DMBO) epoxides as comonomer were investigated in a process compatible with an easy scaling up. Difunctionnal poly(tetrahydrofuran-stat-1,2-butylene oxide)s (PTHF-stat-PBO) and poly(tetrahydrofuran-stat-3,3-dimethyl-1,2-butylene oxide)s (PTHF-stat-PDMBO) were synthesized in the range of 0-20 degrees C using different operating conditions. The reactivity ratios showed a homogeneous distribution of the epoxide units all along the copolymer chains by using BO, while an alternation of several THF and DMBO monomer units sequences was obtained in the DMBO-based copolymers. Still, both copolymerizations fit well with an ideal copolymerization behavior. A slow addition of BO during the propagation step or the introduction of BO or DMBO at the beginning of the polymerization were investigated. Whatever the comonomer used, its insertion in the polymer chain reduced the melting temperature of the copolymers and the impact of the THF polymerization equilibrium on the yields. As a consequence, higher polymerization yields were obtained. A fairly good control of the polymer molar masses was observed, although elimination reactions were highlighted. However, operating conditions were determined to limit the content of the resulting alkene chain ends to about 10%, providing guaranties for further macromolecular architectures developments

Anionic ring-opening polymerization of ethylene oxide in DMF with cyclodextrin derivatives as new initiators

International audienceAnionic polymerization initiated by cyclodextrins suffers from a poor solubility of those derivatives in standard polymerization solvents. The possibility to perform ethylene oxide polymerization initiated by monofunctional initiators (allyl alcohol, 2-methoxyethanol) by living ring opening polymerization in DMF, a good solvent for any CD derivative, was demonstrated by SEC, 1H and 13C NMR analyses. The study was extended to the use of native CD as initiator, leading to the synthesis of ill-defined structures, explained by the reactivity scale of the various hydroxyl functions. Two selectively modified CD derivatives are then used to synthesize a new family of star-shaped poly(ethylene oxide) polymers with CD core, having 14 or 21 arms. The polymerization was found to be living and DOSY experiments confirmed the well-defined structures for the synthesized star-polymers

Synthesis of new biobased linear poly(ester amide)s

International audienceIn the present work, we investigated the synthesis of new biobased linear aliphatic PEAs with a controlled regicity, in a two steps procedure. First, dioldiamide derivatives were successfully synthesized, then polycondensation reaction using the usual alcohol plus acid reaction was performed. NMR analyses demonstrate that dioldiamide can be synthesized in one step from diacid and ethanolamine condensation with high conversion. A new library of polymers was then synthesized, and characterized. Overall, the reactivity of amine or alcohol or acid functions is investigated by in-depth 1 H and 13 C NMR versus HSQC NMR analysis. These results can be used to follow the complex evolution of monoesterification or diesterification reactions, monoamidation or diamidation reactions when dicarboxylic acids versus alcohol or amine are reacted. Thermal degradation was examined, and a good stability of all the polymers was evidenced. The thermal properties of the polymers were also analyzed, and high melting temperatures were measured, thanks to the control of the regicity. Comparing the melting and crystallization temperature revealed a fast rate of crystallization, an important feature for polymer melt processing. The solubility behavior of these polymers was found to be close to the one of polyamides, suggesting the use of this new polymers library to replace polyamides in applications where biodegradability of the materials is required

Supramolecular assemblies of histidinylated α-cyclodextrin in the presence of DNA scaffold during CDplexes formation.

International audienceα-Cyclodextrin was transformed in a cationic unit after per substitution with histidine (His-α-CD) and lysine (Lys-α-CD) molecules on the primary face. His-α-CD and Lys-α-CD were used to form electrostatic complexes (CDplexes) with a plasmid DNA encoding luciferase gene, and the ability of CDplexes to transfect mammalian cells was examined using HEK293-T7 cells. The luciferase activity in cells transfected with His-α-CDplexes was 8-fold higher than that obtained Lys-α-CDplexes. When the transfection was carried out in the presence of chloroquine, the luciferase activity with His-α-CDplexes and Lys-α-CDplexes increased 6 and 25 times, respectively. The lower enhancement with His-α-CDplexes confirmed that histidine induced a proton sponge effect inside endosomes upon imidazole protonation, favoring DNA delivery in the cytosol. At the same time, we found that the condensation of DNA with His-α-CD was unexpectedly stronger than that obtained with the lysyl-α-CD counterpart. Moreover, it was as strong as that observed with high molecular weight polylysine. NMR (ROESY and DOSY) investigations in the absence of DNA showed that an inclusion complex is formed between the imidazole ring of histidine and the hydrophobic cavity of CD but no His-α-CD polymers can be formed by intermolecular interactions. These results suggest that intermolecular interactions between imidazole and His-α-CD cavity could be involved to form supramolecular assemblies in the presence of a DNA scaffold leading to DNA condensation into low diameter particles

Direct Electrografting of Poly(2-alkyl-2-oxazoline)s on Gold, ITO, and Gold Nanoparticles for Biopassivation

International audiencePoly(2-alkyl-2-oxazoline)s (POx) bearing an aminophenyl end group were synthesized by cationic ring-opening polymerization; the polymers were then carefully characterized by NMR, size exclusion chromatography, and differential scanning nano calorimetry. The electroreduction of the diazonium salts of aniline terminated poly(2-methyl-2-oxazoline) (PMeOx) and poly(2-n-propyl-2-oxazoline) (PnPrOx) from aqueous solution on indium tin oxide (ITO) and gold (Au) and through a two-dimensional polystyrene (PS) template has been investigated. On all substrates, ultrathin layers of polymer are grafted and deposited. Modified surfaces were characterized by electrochemistry, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy. Nanoporous honeycomb POx structures have been obtained thanks to electrochemical growth in the interstitial spaces between self-assembled PS spheres. Finally, the wettability of the surfaces depends markedly on the chemical nature of the POx, with contact angles of 32° and 70° for modified surfaces with PMeOx and PnPrO

Synthesis of Linear Polyesters from Monomers Based on 1,18-( Z )-Octadec-9-enedioic Acid and Their Biodegradability

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