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A simple phosgene- and halogen-free method for synthesizing α-amino acid N-carboxyanhydrides (NCAs) is described. The reaction between Boc-protected α-amino acids and T3P reagent gave the corresponding NCA derivatives in good yield and purity with no detectable epimerization. The process is safe, is easy-to-operate, and does not require any specific installation. It generates nontoxic, easy to remove byproducts. It can apply to the preparation of NCAs for the on-demand on-site production of either little or large quantities.

International audience; A simple and efficient way to synthesize peptidecontainingsilicone materials is described. Silicone oils containinga chosen ratio of bioactive peptide sequences wereprepared by acid-catalyzed copolymerization of dichlorodimethylsilane,hybrid dichloromethyl peptidosilane, and Si-(vinyl)- or SiH-functionalized monomers. Functionalized siliconeoils were first obtained and then, after hydrosilylationcross-linking, bioactive polydimethylsiloxane (PDMS)-basedmaterials were straightforwardly obtained. The introductionof an antibacterial peptide yielded PDMS materials showingactivity against Staphylococcus aureus. PDMS containing RGDligands showed improved cell-adhesion properties. This genericmethod was fully compatible with the stability of peptidesand thus opened the way to the synthesis of a widerange of biologically active silicones.

International audience; Synthesis of long peptides is generally considered as being a challenge to peptide chemists, in addition to producing significant amounts of toxic waste, such as DMF. Here we show that using solvent-less methods, such as ball milling, enabled the production of the hexapeptide Boc-(Ala-Phe-Gly)2-OBn at the gram scale with high overall yield (77%, 5 linear steps). This is the longest peptide chain synthesized in a ball mill to date, in which the amino acid sequence is precisely controlled. This study complements the current fundamental knowledge required to synthesize longer and more difficult peptide chains (or small proteins) by using peptide fragment couplings in a ball mill.

Thanks to their wide range of biological activities, peptides have been extensively used to afford designed materials with tailored properties. Peptides can be associated to polymers combining the properties of various polymer backbones with those of bioactive peptide sequences. Such conjugates find promising applications in medical devices, tissue engineering, drug targeting and delivery. Improvement of existing polymers by post-modification peptide grafting is achieved through an extensive range of organic reactions, involving the prior preparation of functional polymers displaying suitable anchoring functions. Alternatively, peptides can be used as initiators of polymerization yielding a chimeric molecule bearing a single peptide at the end of macromolecular chains. Finally, novel polymer materials can be designed when the peptide itself is used as a macromonomer. In that case, the unmatched level of repetition of the peptide sequence or/and its self-assembly properties allow to access very high functionalization degree, original structures and bioactivities.

International audience; Peptides were produced in high yields and, if any, very low epimerization, by mechanochemical coupling of peptide fragments containing highly epimerization-prone and/or highly hindered amino acids at C-term. Ball milling was clearly identified as the key element enabling one to obtain such results.

International audience; (R)-1,2-Diaminobicyclo[2.2.2]octane was used as a starting material for the preparation, in solution or in a ball mill, of a salen ligand. Five metal salen complexes were prepared in high yield and their cytotoxic activities were evaluated against the Human Colon cancer HCT116 cell lines. The original manganese salen complex displayed the highest activity with a potency 16 fold higher than that of cisplatin, demonstrating the benefit of the bridging backbone compared to other salen systems. An alternative preparation route for this complex by mechanochemistry was also performed.

International audience; The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT6R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Nonphysiological activation of mTOR kinase by constitutively active 5-HT6R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT6R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT6R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats.

New synthetic textiles with physical and/or biological properties are increasingly used in medical applications [1,2]. While a simple textile coating is usually carried out to obtain biological properties, covalent grafting should be considered for long-term applications. Herein, we have developed a new hybrid bioactive nylon whose synthesis involves a peptide sequence with a diacyl derivative. Numerous types of peptide-nylons were prepared by varying the molar percentage (0.1%, 1% and 10%) and orientation of the peptide in the polymer backbone. Nylons incorporating antibacterial peptides significantly inhibited S. aureus proliferation whereas nylons functionalized with cell-adhesive peptide enhanced the proliferation of L929 fibroblast. These results show that the incorporation of the peptides directly into the nylon skeleton is efficient and provides biological properties that suggest new ways of functionalizing biomedical textiles.

International audience; More than 160 arginine analogues modified on the C‐terminus via either an amide bond or a heterocyclic moiety (1,2,4‐oxadiazole, 1,3,4‐oxadiazole and 1,2,4‐triazole) were prepared as potential inhibitors of NO synthases (NOS). A methodology involving formation of a thiocitrulline intermediate linked through its side‐chain on a solid support followed by modification of its carboxylate group was developed. Finally, the side‐chain thiourea group was either let unchanged, S‐alkylated (Me, Et) or guanidinylated (Me, Et) to yield respectively after TFA treatment the corresponding thiocitrulline, S‐Me/Et‐isothiocitrulline and N‐Me/Et‐arginine substrate analogues. They all were tested against three recombinant NOS isoforms. Several compounds containing a S‐Et‐ or a S‐Me‐Itc moiety and mainly belonging to both the dipeptide‐like and 1,2,4‐oxadiazole series were shown to inhibit nNOS and iNOS with IC50 in the 1–50 μM range. Spectral studies confirmed that these new compounds interacted at the heme active site. The more active compounds were found to inhibit intra‐cellular iNOS expressed in RAW264.7 and INS‐1 cells with similar efficiency than the reference compounds L‐NIL and SEIT.

Non-cationic and amphipathic indoloazepinone-constrained (Aia) oligomers have been synthesized as new vectors for intracellular delivery. The conformational preferences of the [l-Aia-Xxx]n oligomers were investigated by circular dichroism (CD) and NMR spectroscopy. Whereas Boc-[l-Aia-Gly]2,4 -OBn oligomers 12 and 13 and Boc-[l-Aia-β3 -h-l-Ala]2,4 -OBn oligomers 16 and 17 were totally or partially disordered, Boc-[l-Aia-l-Ala]2 -OBn (14) induced a typical turn stabilized by C5 - and C7 -membered H-bond pseudo-cycles and aromatic interactions. Boc-[l-Aia-l-Ala]4 -OBn (15) exhibited a unique structure with remarkable T-shaped π-stacking interactions involving the indole rings of the four l-Aia residues forming a dense hydrophobic cluster. All of the proposed FITC-6-Ahx-[l-Aia-Xxx]4 -NH2 oligomers 19-23, with the exception of FITC-6-Ahx-[l-Aia-Gly]4 -NH2 (18), were internalized by MDA-MB-231 cells with higher efficiency than the positive references penetratin and Arg8 . In parallel, the compounds of this series were successfully explored in an in vitro blood-brain barrier (BBB) permeation assay. Although no passive diffusion permeability was observed for any of the tested Ac-[l-Aia-Xxx]4 -NH2 oligomers in the PAMPA model, Ac-[l-Aia-l-Arg]4 -NH2 (26) showed significant permeation in the in vitro cell-based human model of the BBB, suggesting an active mechanism of cell penetration.

New chiral tetra- and bidentate ligands derived from the (R)-1,2-diaminobicyclo[2.2.2]octane scaffold have been synthesized and the influence of ligand N,N'-substituents on the catalytic activity of their corresponding copper(II) complexes toward nitroaldol reaction have been investigated. Among them, the complex generated in situ by the interaction of the (R)-N,N'-Bis(1-naphthylmethyl)-1,2-diaminobicyclo[2.2.2]octane ligand L10 with Cu(OAc)2 proved to be the most effective for the asymmetric Henry reaction of nitromethane with various aldehydes, providing b-nitroalcohols in moderate to good yields, and enantioselectivity (up to 86%). In an attempt to rationalize the factors that control enantiodifferentiation, the most stable geometries of this C1-symmetric bicyclic copper ligand complex, as well as plausible transition structures of the nitroaldol reaction, were investigated by DFT calculations.

International audience; Promising strategies for cartilage regeneration rely on the encapsulation of mesenchymal stromal cells (MSCs) in a hydrogel followed by an injection into the injured joint. Preclinical and clinical data using MSCs embedded in a collagen gel have demonstrated improvements in patients with focal lesions and osteoarthritis. However, an improvement is often observed in the short or medium term due to the loss of the chondrocyte capacity to produce the correct extracellular matrix and to respond to mechanical stimulation. Developing novel biomimetic materials with better chondroconductive and mechanical properties is still a challenge for cartilage engineering. Herein, we have designed a biomimetic chemical hydrogel based on silylated collagen-mimetic synthetic peptides having the ability to encapsulate MSCs using a biorthogonal sol-gel cross-linking reaction. By tuning the hydrogel composition using both mono- and bi-functional peptides, we succeeded in improving its mechanical properties, yielding a more elastic scaffold and achieving the survival of embedded MSCs for 21 days as well as the up-regulation of chondrocyte markers. This biomimetic long-standing hybrid hydrogel is of interest as a synthetic and modular scaffold for cartilage tissue engineering.

International audience; Combined therapy is a global strategy developed to prevent drug resistance in cancer and infectious diseases. In this field, there is a need of multifunctional drug delivery systems able to co-encapsulate small drug molecules, peptides, proteins, associated to targeting functions, nanoparticles. Silylated hydrogels are alkoxysilane hybrid polymers that can be engaged in a sol-gel process, providing chemical cross linking in physiological conditions, and functionalized biocompatible hybrid materials. In the present work, microgels were prepared with silylated (hydroxypropyl)methyl cellulose (Si-HPMC) that was chemically cross linked in soft conditions of pH and temperature. They were prepared by an emulsion templating process, water in oil (W/O), as microreactors where the condensation reaction took place. The ability to functionalize the microgels, so-called FMGs, in a one-pot process, was evaluated by grafting a silylated hydrophilic model drug, fluorescein (Si-Fluor), using the same reaction of condensation. Biphasic microgels (BPMGs) were prepared to evaluate their potential to encapsulate lipophilic model drug (Nile red). They were composed of two separate compartments, one oily phase (sesame oil) trapped in the cross linked Si-HPMC hydrophilic phase. The FMGs and BPMGs were characterized by different microscopic techniques (optic, epi-fluorescence, Confocal Laser Scanning Microscopy and scanning electronic microscopy), the mechanical properties were monitored using nano indentation by Atomic Force Microscopy (AFM), and different preliminary tests were performed to evaluate their chemical and physical stability. Finally, it was demonstrated that it is possible to co-encapsulate both hydrophilic and hydrophobic drugs, in silylated microgels, that were physically and chemically stable. They were obtained by chemical cross linking in soft conditions, and without surfactant addition during the emulsification process. The amount of drug loaded was in favor of further biological activity. Mechanical stimulations should be necessary to trigger drug release.

The recently described homoleptic cationic [Ag(IPr)2]PF6 [IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolylidene] complex proved to be a versatile and highly efficient catalyst for the production of propargylamines by using the A3-coupling reaction. The reaction conditions were equally applicable to aliphatic and aromatic aldehydes and alkynes, including highly hindered aromatic aldehydes. Progargylamines were prepared in short reaction times with low catalyst loadings by using MeOH as a low-toxicity solvent. In addition, the catalyst was stable enough to support continuous-flow conditions, which showed that the reaction conditions are scalable.

Angiotensin converting enzyme (ACE) is a well-known enzyme, largely studied for its action on hypertension, as it produces angiotensin II from angiotensin I. This paper describes two original behaviours of ACE. We showed that ACE could hydrolyse gastrin, a neuropeptide from the gastrointestinal tract, releasing the C-terminal amidated dipeptide H-Asp-Phe-NH2 . This dipeptide is believed to be involved in the gastrin-induced acid secretion in the stomach. This hypothetic mechanism of action of gastrin resulted in a strategy to rationally design gastrin receptor antagonists. Beyond, we showed that the brain renin angiotensin system (RAS) could be activated by a new characterized peptide named acein, resulting in stimulation of dopamine release within the striatum. This new and original 'receptor-like' activity for brain membrane-bound ACE is quite significant taking into account the role of dopamine in the brain, particularly in neurodegenerative diseases. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Few decades ago, the expertise gained from well-established extraction, processing and degradation techniques, paved the way for the use of ultrasounds as an alternative energy source in chemistry. Among other peculiar features, the locally extreme temperatures and pressures resulting from cavitation, proved to efficiently trigger reactions while maintaining mild average conditions, enhancing rates and yields and, hence, contributing to increase the popularity of sonochemistry up to the present level. The physical properties of the irradiated mixture are crucial for the effectiveness of cavitation, as well as for the proper transfer of acoustic energy to reactants. Therefore, the choice of a solvent that meets these requirements, while minimizing the environmental impact of the process is a fundamental one. Studies that combine sonochemistry with green, non-conventional solvents or with no solvents are surveyed in this review, evidencing how the most frequently investigated options are water phase, ionic liquids, followed by ethylene glycol and its oligomers, glycerol and few other biomass-based solvents. Numerous solvent-free, ultrasound-promoted procedures are also reported in the literature and are included in this contribution. The vast majority of the examples gathered here describe organic reactions, syntheses of nanosystems and polymerizations.

A stereoconservative three-step synthesis to access to 1,2,4-oxadiazine-3,6-dione is presented. This underexplored platform could be considered as a constrained oxy-azapeptide or an aza-diketomorpholine, the methodology being then successfully applied to produce enantiopure aza-analogs of diketomorpholine natural products. Importantly, the first crystal structures were obtained and compared to diketomorpholine and diketopiperazine structures. Finally, a straightforward procedure concerning the coupling of this heterocyclic scaffold with various amino acids to afford original pseudodipeptide analogs was described.

We recently described a pyrido-imidazodiazepinone derivative which could be a promising hit compound for the development of new drugs acting against melanoma cells. In this study, a series of 28 novel pyrido-imidazodiazepinones were synthesized and screened for their in vitro cytotoxic activities against the melanoma MDA-MB-435 cell line. Among the derivatives, seven of them showed 50% growth inhibitory activity at 1 μM concentration, and high selectivity against the melanoma cell line MDA-MB-435.

In this study we describe a Nazarov cyclization of activated dienones bearing an aromatic moiety as EDG and a chiral sulfoxide group both as an EWG and a chiral inductor. The sulfinyl group directed the torquoselectivity, and AlCl3 was used as a promoter. Only both trans stereoisomers were observed. Substrates bearing activated aromatic moieties including phenyl and aromatic heterocycles led to the desired cyclopentanones. The potential of this methodology was highlighted by the first enantioselective synthesis of two anticancer agents.

The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their main biological activities.

International audience; 5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives were prepared by mechanochemistry from amino esters or dipeptides, via a 1,1′-carbonyldiimidazole-mediated one-pot/two-step cyclization reaction involving amino acid unsymmetrical urea A and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution were also performed. The successful preparation of an antibacterial agent precursor was also investigated.

Protein arginine N-methyl transferases (PRMTs) belong to a family of enzymes that modulate the epigenetic code through modifications of histones. In the present study, peptides emerging from a phage display screening were modified in the search for PRMT inhibitors through substitution with non-proteinogenic amino acids, N-alkylation of the peptide backbone, and incorporation of constrained dipeptide mimics. One of the modified peptides (23) showed an increased inhibitory activity towards several PRMTs in the low μm range and the conformational preference of this peptide was investigated and compared with the original hit using circular dichroism and NMR spectroscopy. Introducing two constrained tryptophan residue mimics (l-Aia) spaced by a single amino acid was found to induce a unique turn structure stabilized by a hydrogen bond and aromatic π-stacking interaction between the two l-Aia residues.

A concise synthesis of ( S )-γ-fluoroleucine is described in five steps from commercially available compounds, with an overall yield of 57%. The Markovnikov hydrofluorination reaction of the unsaturated amino acid precursor as last step of the synthesis proved to be effective. This fluorination can also be performed directly on a short peptide model with the same efficiency. This reaction could be in principle applicable for the preparation of radiolabeled amino acids and peptides.

The O-N acyl transfer reaction has gained significant popularity in peptide and medicinal chemistry. This reaction has been successfully applied to the synthesis of difficult sequence-containing peptides, cyclic peptides, epimerization-free fragment coupling and more recently, to switchable peptide polymers. Herein, we describe a related strategy to facilitate the synthesis and purification of a hydrophobic stapled peptide. The staple consists of a serine linked through an amide bond formed from its carboxylic acid function and the side chain amino group of diaminopropionic acid and through an ester bond formed from its amino group and the side chain carboxylic acid function of aspartic acid. The α-amino group of serine was protonated during purification. Interestingly, when the peptide was placed at physiological pH, the free amino group initiated the O-N shift reducing the staple length by one atom, leading to a more hydrophobic stapled peptide.

International audience; Mechanochemistry was effective for the preparation of 3,5-disubstituted hydantoins from a-amino methyl esters, using either 1,1 0-carbonyldiimidazole (CDI) or alkyl isocyanates. The preparation of the antimicrobial additives, 3-allyl-5,5 0-dimethyl hydantoin (ADMH) and 1-chloro-3-ethyl-5,5 0-dimethyl hydantoin (CEDMH) were performed by grinding. A chlorination reaction, never described before by mechanochemistry was achieved by Ca(ClO) 2 , while the preparation of the bioactive anticonvulsant marketed drug ethotoin was achieved by a novel approach based on poly(ethylene) glycol (PEGs) assisted grinding.

In the search for new peptide ligands containing selenium in their sequences, we investigated l-4-selenazolidine-carboxylic acid (selenazolidine, Sez) as a proline analog with the chalcogen atom in the γ-position of the ring. In contrast to proteinogenic selenocysteine (Sec) and selenomethionine (SeMet), the incorporation within a peptide sequence of such a non-natural amino acid has never been studied. There is thus a great interest in increasing the possibility of selenium insertion within peptides, especially for sequences that do not possess a sulfur containing amino acid (Cys or Met), by offering other selenated residues suitable for peptide synthesis protocols. Herein, we have evaluated selenazolidine in Boc/Bzl and Fmoc/tBu strategies through the synthesis of a model tripeptide, both in solution and on a solid support. Special attention was paid to the stability of the Sez residue in basic conditions. Thus, generic protocols have been optimized to synthesize Sez-containing peptides, through the use of an Fmoc-Xxx-Sez-OH dipeptide unit. As an example, a new analog of the vasopressin receptor-1A antagonist was prepared, in which Pro was replaced with Sez [3-(4-hydroxyphenyl)-propionyl-d-Tyr(Me)-Phe-Gln-Asn-Arg-Sez-Arg-NH2]. Both proline and such pseudo-proline containing peptides exhibited similar pharmacological properties and endopeptidase stabilities indicating that the presence of the selenium atom has minimal functional effects. Taking into account the straightforward handling of Sez as a dipeptide building block in a conventional Fmoc/tBu SPPS strategy, this result suggested a wide range of potential uses of the Sez amino acid in peptide chemistry, for instance as a viable proline surrogate as well as a selenium probe, complementary to Sec and SeMet, for NMR and mass spectrometry analytical purposes.

12/10-Helices constitute suitable templates that can be used to design original structures. Nevertheless, they often suffer from a weak stability in polar solvents because they exhibit a mixed hydrogen-bond network resulting in a small macrodipole. In this work, stable and functionalizable 12/10-helices were developed by alternating a highly constrained β2, 3, 3 -trisubstituted bicyclic amino acid (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid ((S)-ABOC) and an acyclic substituted β-homologated proteinogenic amino acid (l-β3 -hAA). Based on NMR spectroscopic analysis, it was shown that such mixed β-peptides display well-defined right-handed 12/10-helices in polar, apolar, and chaotropic solvents; that are, CD3 OH, CDCl3 , and [D6 ]DMSO, respectively. The stability of the hydrogen bonds forming the C10 and C12 pseudocycles as well as the benefit provided by the use of the constrained bicyclic ABOC versus typical acyclic β-amino acids sequences when designing 12/10-helix were investigated using NH/ND NMR exchange experiments and DFT calculations in various solvents. These studies showed that the β3 -hAA/(S)-ABOC helix displayed a more stable hydrogen-bond network through specific stabilization of the C10 pseudocycles involving the bridgehead NH of the ABOC bicyclic scaffold.

International audience; 1,4-Disubstituted-1,2,3-triazole (Tz) is widely used in peptides as a trans-amide bond mimic, despite having hazardous effects on the native peptide activity. The impact of amide bond substitution by Tz on peptide secondary structures is scarcely documented. We performed a Tz scan, by systematically replacing peptide bonds following the Aib residues with Tz on two model peptaibols: alamethicin F50/5 and bergofungin D, which adopt stable α- and 310 helices, respectively. We observed that the Tz insertion, whatever its position in the peptide sequences, abolished their antimicrobial activity. The structural consequences of this insertion were further investigated using CD, NMR and X-ray diffraction. Importantly, five crystal structures that were incorporated with Tz were solved, showing various degrees of alteration of the helical structures, from minor structural perturbation of the helix to partial disorder. Together, these results showed that Tz insertions impair helical secondary structures.

International audience; A new ring contraction of fused bis-lactams into spirolactams is presented here. In the presence of a triflate catalyst in various solvents under microwave irradiation, this rearrangement allows a clean conversion of some fused bicycles into spirocycles with good yields. The interest of this work thus lies in the use of activated 2,5-diketopiperazines as starting materials and demonstrates the wide range of applications of ring contraction reactions

International audience; According to their restricted conformational freedom, heterocyclic -amino acids are usually considered to be related to Z-vinylogous -amino acids. In this context, oligomers alternating -amino acids and thiazole-based -amino acids (ATCs) were expected to fold into a canonical 12-helical shape as described for /-hybrid peptides composed of cis-/-unsaturated -amino acids. However, through a combination of X-ray crystallography, NMR spectroscopy, FTIR experiments, and DFT calculations, it was determined that the folding behavior of ATC-containing hybrid peptides is much more complex. The homochiral /(S)-ATC sequences were unable to adopt a stable conformation, whereas the heterochiral /(R)-ATC peptides displayed novel ribbon structures stabilized by unusual C-9/12-bifurcated hydrogen bonds. These ribbon structures could be considered as a succession of pre-organized / dipeptides and may provide the basis for designing original -helix mimics.

Herein, we describe an approach to cage metallasilsesquioxanes by self-assembly with 1,2-bis(diphenylphosphino)ethane as a key reactant. This approach allowed us to achieve a unique family of complexes that includes anionic tetra- and nonanuclear cage copper(II) sodium silsesquioxane and cationic copper(I) 1,2-bis(diphenylphosphino)ethane components. Additional representatives of this intriguing metallasilsesquioxane family (Cu9Na6 and Cu9Na3Cs3) were obtained through the replacement of the original ethanol-based reaction medium by DMSO. The fascinating structural peculiarities of all products were established by using XRD and topological studies. Initial tests for the application of the synthesized complexes as catalysts revealed their very high activity in the homogeneous oxidation of alkanes and alcohols to produce alkyl hydroperoxides, ketones, and amides.

International audience; The absence of solvent, associated with intensive mechanical agitation, allowed the first mechanosynthesis of high-value silver(I)-carbenec omplexes and the corresponding N,N-dialkylimidazolium precursors. This procedure gave outstanding results in terms of yield and reactiont ime, when compared to solution-based conditions previously described in literature, and was generalized to unprecedented compounds. Silver(I)-carbene complexes could either be obtainedf rom N,N-dialkylimidazolium salts or directly from imidazole and alkyl halides in ao ne-pot two-step procedure withouti solating the imidazolium intermediate. Additionally,a ne fficient one-pot three-step sequence, including imidazole alkylation, silver metalation, andtransmetalationi sr eported.

A series of 5-substituted thieno[3,2-e][1,4]diazepin-2-ones was synthesized in four steps from methyl 3-aminothiophene-2-carboxylate. After the coupling of 3-aminothiophene with α-amino acids, the key final step that involves an uncatalysed Pictet–Spengler reaction allowed the cyclization of the seven-membered diazepinone ring. The reaction was first optimized and then exemplified in three different series (phenylalanine, alanine and proline) that led to 24 target diazepinones, which includes 19 optically pure diastereomers.

Structured peptides gained more attention over a decade because of their biological properties, biocompatibility and ability to act as modulators of protein/protein interactions, antibiotics, analgesics, immunosuppressants or as imaging agents to cite a few relevant applications. However, their poor bioavalability due in part to the susceptibility of the peptide bond to proteolytic cleavages often impaired their development and considerably limited their therapeutic use. To circumvent these problems, many efforts are undertaken to discover stable amide bond mimics resistant to proteolytic degradation. Among them the 1,2,3 triazole emerged as a highly stable analogue of the trans-peptide bond to generate bioactive peptides. Here we report a convenient approach to readily substitute amide bonds by triazole rings in Aib-containing peptides using Aibψ[Tz]-Xaa dipeptide-like units. We defined their application in solid phase synthesis and generated short model peptide sequences to study the impact of the triazole incorporation on their conformations in solution by CD and NMR spectroscopies. This article is protected by copyright. All rights reserved.

The transmetalation of bimetallic copper-sodium silsesquioxane cages, namely, [(PhSiO1.5 )10 (CuO)2 (NaO0.5 )2 ] ("Cooling Tower"; 1), [(PhSiO1.5 )12 (CuO)4 (NaO0.5 )4 ] ("Globule"; 2), and [(PhSiO1.5 )6 (CuO)4 (NaO0.5 )4 (PhSiO1.5 )6 ] ("Sandwich"; 3), resulted in the generation of three types of hexanuclear cylinder-like copper silsesqui- oxanes, [(PhSiO1.5 )12 (CuO)6 (C4 H9 OH)2 (C2 H5 OH)6 ] (4), [(PhSiO1.5 )12 (CuO)6 (C4 H8 O2 )4 (PhCN)2 (MeOH)4 ] (5), and [(PhSiO1.5 )12 (CuO)6 (NaCl)(C4 H8 O2 )12 (H2 O)2 ] (6). The products show a prominent "solvating system-structure" dependency, as determined by X-ray diffraction. Topological analysis of cages 1-6 was also performed. In addition, DFT theory was used to examine the structures of the Cooling Tower and Cylinder compounds, as well as the spin density distributions. Compounds 1, 2, and 5 were applied as catalysts for the direct oxidation of alcohols and amines into the corresponding amides. Compound 6 is an excellent catalyst in the oxidation reactions of benzene and alcohols.

4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are a new class of constrained heterocyclic γ-amino acids built around a thiazole ring; these compounds are valuable as design mimics of the secondary structures of proteins such as helices, β-sheets, turns, and β-hairpins. We report herein a short and versatile chemical route to orthogonally protected ATCs. The synthesis is centered on cross-Claisen condensations between N-Fmoc-amino acids and sterically hindered 1,1-dimethylallyl acetate. The optimized conditions are compatible with aliphatic, aromatic, acidic, and basic amino acids. The resulting N-Fmoc-β-keto ester intermediates were engaged in a two-step process to give ATCs in 45–90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ-carbon atom or on the thiazole core of the γ-amino acids.

We have recently reported on a new class of silicone–peptide‵ biopolymers obtained by polymerization of di-functionalized chlorodimethylsilyl hybrid peptides. Herein, we describe a related strategy based on dichloromethylsilane-derived peptides, which yield novel polymers with a polysiloxane backbone, comparable with a silicone-bearing pendent peptide chains. Interestingly, polymerization is chemoselective toward amino acids side-chains and proceeds in a single step in very mild conditions (neutral pH, water, and room temperature). As potential application, a cationic sequence was polymerized and used for antibacterial coating. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

The application of mechanical forces to enable a chemical reaction, also known as mechanochemistry, is actually experiencing an impressive renewal of interest among the chemists community. One major advantage of this approach in organic synthesis lies in the possibility to run essentially solvent-free reactions. In recent years, some research groups have combined these types of solvent-free processes with the use of an eco-friendly reagent: 1,1′-carbonyldiimidazole (CDI). Thus, a wide range of molecules, including carboxylic acids, amines, and alcohols, could react efficiently with CDI under ball-milling conditions. By providing a vast array of products (amides, carboxylic acids, esters, ureas, hydantoins, etc.) in an efficient, fast, user-friendly, and green manner, this approach presents all the prerequisites to soon become a first choice methodology for all organic chemists. The reasons for the past and future successes of this combination are summarized, analyzed, and discussed herein.

International audience; Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subsequently , the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline-proline dipeptides under solvent-free conditions. A deprotection-cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstituted Pro-Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill. 2169

Different intracellular delivery systems of bioactive compounds have been developed, including cell-penetrating peptides. While usually non-toxic and biocompatible, these vectors share some of the general peptide drawbacks, notably low bioavailability and susceptibility to protease degradation that limit their use. Here, we investigated the conversion of short peptide sequences into poly-α-amino-γ-lactam (Agl-AA) foldamers that adopted a ribbon-like structure. We used this template to distribute critical cationic and/or hydrophobic groups on both sides of their backbones, leading to potent short cell-permeable foldamers with low positive charge content. The lead compound showed dramatically improved protease resistance and was able to efficiently deliver a biologically relevant cargo inside the cell. This study provided a simple strategy to convert short peptide sequences into efficient protease-resistant cell-penetrating foldamers.

We propose a simple and efficient strategy to significantly improve the antibacterial activity of peptaibols and other antimicrobial peptides by N-terminal capping with 1,2,3-triazole bearing various hydrophobic substituents on C-4. We showed, herein, that such N-terminal insertions on alamethicin F50/5 could enhance its antimicrobial activity on gram-positive bacteria without modification of its overall three-dimensional structure. Indeed, while the native peptide and its analogues shared comparable helical contents, the crystal structure of one of the most active derivative showed a local slight distortion of the N-terminal extremity, which was also observed in solution using NMR spectroscopy. Importantly, fluorescence studies showed that the N-capped derivatives had increased affinity for liposomes which may indicate they interacted more strongly with the bacterial membrane than alamethicin F50/5.

52nd International Conference on Medicinal Chemistry (RICT) of the French-Medicinal-Chemistry-Society (SCT) - Interfacing Chemical Biology and Drug Discovery -- JUL 06-08, 2016 -- Caen, FRANCE, WOS: 000403905300014, PubMed ID: 28505394, Metallo-beta-lactamases (MBLs) cause resistance of Gram-negative bacteria to beta-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3D structures suggested that the triazolethione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 mm range., French Med Chem Soc, Univ Caen, Agence Nationale de la Recherche ("ANTIMBL") [ANR-14-CE16-0028-01]; Deutsche Forschungsgemeinschaft [BE1540/15-2 within SPP 1710]; Agence Nationale de la Recherche [ANR-06-BLAN-0086], We thank Mr. Pierre Sanchez for mass spectrometry analyses and Wolfram Meyer-Klaucke for advice about tRNase Z. Part of this work was supported by the Agence Nationale de la Recherche ("ANTIMBL", ANR-14-CE16-0028-01, including a fellowship to L.S.), the Deutsche Forschungsgemeinschaft (BE1540/15-2 within SPP 1710 to K.B.), and Agence Nationale de la Recherche ("subtilRNA", ANR-06-BLAN-0086) to C.C.