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The mechanism of the asymmetric addition of aldehyde (butanal) to nitroolefin (β-nitrostyrene) catalyzed by H-d-Pro-Pro-Glu-NH2 (dPPE-NH2; 1) was explored using density functional theory methods in chloroform. By conformational search, it was confirmed that catalyst 1 and its enamine intermediate adopted a dominant conformation with a βI structure stabilized by a C10 H-bond between the C═O of d-Pro1 and C-terminal NH2 proton and by an additional H-bond between the side chain and the backbone of Glu3. This βI turn structure was conserved all along the catalytic cycle. Consistently with the kinetic studies, the C–C bond formation between the enamine and electrophile was also confirmed as the rate-determining step. The stereoselectivity results from a re → re prochiral approach of enamine and β-nitrostyrene with a gauche– orientation of the double bonds. Although it was suggested as the possible formation of dihydrooxazine oxide species, this process was confirmed to be kinetically less accessible than the f...

International audience; As three‐dimensional folding is prerequisite to biopolymer activity, complex functions may also be achieved through foldamer science. Because of the diversity of sizes, shapes and folding available with synthetic monomers, foldamer frameworks enable a numerous opportunities for designing new generations of catalysts. We herein demonstrate that heterocyclic γ‐peptide scaffolds represent a versatile platform for enamine catalysis. One central feature was to determine how the catalytic activity and the transfer of chiral information might be under the control of the conformational behaviours of the oligomer.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) belong to the 10 deadliest diseases and are sorely lacking in effective treatments. Both pathologies are part of the degenerative disorders named amyloidoses, which involve the misfolding and the aggregation of amyloid peptides, hIAPP for T2D and Aβ1-42 for AD. While hIAPP and Aβ1-42 inhibitors have been essentially designed to target β-sheet-rich structures composing the toxic amyloid oligomers and fibrils of these peptides, the strategy aiming at trapping the non-toxic monomers in their helical native conformation has been rarely explored. We report herein the first example of helical foldamers as dual inhibitors of hIAPP and Aβ1-42 aggregation and able to preserve the monomeric species of both amyloid peptides. A foldamer composed of 4-amino(methyl)-1,3-thiazole-5-carboxylic acid (ATC) units, adopting a 9-helix structure reminiscent of 310 helix, was remarkable as demonstrated by biophysical assays combining thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis and mass spectrometry.

Sugars play key roles in many molecular and cellular communication processes involving a family of proteins named lectins. The low affinity associated with sugar recognition is generally counterbalanced by the multivalent nature of the interaction. While many polyglycosylated architectures have been described, only a few studies focused on the impact of topology variations of the multivalent structures on the interaction with lectin proteins. One major interest of our group concerns the design of new highly predictable and stable molecular pseudo-peptide architectures for therapeutic applications. In such a context, we described a class of constrained heterocyclic γ-amino acids built around a thiazole ring, named ATCs. ATC oligomers are helical molecules resulting from the formation of a highly stable C9 hydrogen-bonding pattern. Following our program, we herein address the potential of ATC oligomers as tunable scaffolds for the development of original multivalent glycoclusters.

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.

The mechanism of the asymmetric addition of aldehyde (butanal) to nitroolefin (β-nitrostyrene) catalyzed by H-d-Pro-Pro-Glu-NH2 (dPPE-NH2; 1) was explored using density functional theory methods in chloroform. By conformational search, it was confirmed that catalyst 1 and its enamine intermediate adopted a dominant conformation with a βI structure stabilized by a C10 H-bond between the C=O of d-Pro1 and C-terminal NH2 proton and by an additional H-bond between the side chain and the backbone of Glu3. This βI turn structure was conserved all along the catalytic cycle. Consistently with the kinetic studies, the C–C bond formation between the enamine and electrophile was also confirmed as the rate-determining step. The stereoselectivity results from a re → re prochiral approach of enamine and β-nitrostyrene with a gauche– orientation of the double bonds. Although it was suggested as the possible formation of dihydrooxazine oxide species, this process was confirmed to be kinetically less accessible than the formation of acyclic nitronate. In particular, our calculated results supported that the carboxylic acid group of Glu3 in 1 played a central role by acting as general acid/base all along the catalytic cycle and orienting the asymmetric C–C bond formation.

Enzymes are predominantly proteins able to effectively and selectively catalyze highly complex biochemical reactions in mild reaction conditions. Nevertheless, they are limited to the arsenal of reactions that have emerged during natural evolution in compliance with their intrinsic nature, three-dimensional structures and dynamics. They optimally work in physiological conditions for a limited range of reactions, and thus exhibit a low tolerance for solvent and temperature conditions. The de novo design of synthetic highly stable enzymes able to catalyze a broad range of chemical reactions in variable conditions is a great challenge, which requires the development of programmable and finely tunable artificial tools. Interestingly, over the last two decades, chemists developed protein secondary structure mimics to achieve some desirable features of proteins, which are able to interfere with the biological processes. Such non-natural oligomers, so called foldamers, can adopt highly stable and predictable architectures and have extensively demonstrated their attractiveness for widespread applications in fields from biomedical to material science. Foldamer science was more recently considered to provide original solutions to the de novo design of artificial enzymes. This review covers recent developments related to peptidomimetic foldamers with catalytic properties and the principles that have guided their design.

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.

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.

According to their restricted conformational freedom, heterocyclic γ-amino acids are usually considered to be related to Z-vinylogous γ-amino acids. In this context, oligomers alternating α-amino acids and thiazole-based γ-amino acids (ATCs) were expected to fold into a canonical 12-helical shape as described for α/γ-hybrid peptides composed of cis-α/β-unsaturated γ-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 α/(S)-ATC sequences were unable to adopt a stable conformation, whereas the heterochiral α/(R)-ATC peptides displayed novel ribbon structures stabilized by unusual C

A convenient synthesis of pyrrolo[3,2- d ][1,3]oxazine-2,4-dione 4 is described and its reactivity towards various nucleophiles studied. The regioselective ring opening of anhydride 4 or its N -alkylated analog 25 in the presence of alanine or proline afforded, respectively, imidazolidinedione 22 and N -protected pyrrolo[3,2- e ][1,4]diazepines 30 and 31 in a one-pot process. In a last part of this study, an alternative route to produce a library of eight non protected pyrrolo[3,2- e ][1,4]diazepine-2,5-diones 35a – h is described to overcome the limited reactivity of anhydride 4 .

9-Helix: 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) were synthesized as new γ-amino acid building blocks. The structures of various ATC oligomers were analyzed in solution by CD and NMR spectroscopy and in the solid state by X-ray crystallography. The ATC sequences adopted a well-defined 9-helix structure in the solid state and in aprotic and protic organic solvents as well as in aqueous solution.

We herein report the synthesis of a series of 12 optically pure 3,4-dihydro-1H-pyrido-[1′,2′:1,2]-imidazo[4,5-d][1,3]diazepine-2,5-diones, which form a new family of azaheterocycle-fused [1,3]diazepines. The key step of the synthesis consists in a selective C-acylation of 2-amino-imidazo[1,2-a]pyridine by various natural amino-acids, followed by an intracarbonylation reaction.

A series of 20 optically pure 3,4-dihydro-5H-pyrido[1',2':1,2]imidazo[4,5-d][1,3]diazepin-5-ones which form a new family of azaheterocycle-fused [1,3]diazepines were synthesized in four steps with 17-66% overall yields. The key step consists of a selective C-acylation reaction of easily accessible 2-aminoimidazo[1,2-a]pyridine at C-3.

International audience; A straightforward and traceless solid-phase methodology was developed for the synthesis of isocoumarins. This two-step process involves a Sonogashira cross-coupling reaction between polymer-bound 2-bromobenzoates and terminal alkynes, followed by an electrophile-induced halocyclization of the resulting 2-(alk-1-ynyl)benzoates through activation of the triple bond with the subsequent release of the 3-substituted 4-haloisocoumarins. This polymer-bound parallel synthetic approach allowed us to achieve large diversity in good to excellent yields and purities.

International audience; Mass spectrometry, and especially electrospray ionization, is now an efficient tool to study noncovalent interactions between proteins and inhibitors. It is used here to study the interaction of some weak inhibitors with the NCoA-1/STAT6 protein with KD values in the M range. High signal intensities corresponding to some nonspecific electrostatic interactions between NCoA-1 and the oppositely charged inhibitors were observed by nanoelectrospray mass spectrometry, due to the use of high ligand concentrations. Diverse strategies have already been developed to deal with nonspecific interactions, such as controlled dissociation in the gas phase, mathematical modeling, or the use of a reference protein to monitor the appearance of nonspecific complexes. We demonstrate here that this last methodology, validated only in the case of neutral sugar-protein interactions, i.e., where dipole- dipole interactions are crucial, is not relevant in the case of strong electrostatic interactions. Thus, we developed a novel strategy based on half-maximal inhibitory concentration (IC50) measurements in a competitive assay with readout by nanoelectrospray mass spectrometry. IC50 values determined by MS were finally converted into dissociation constants that showed very good agreement with values determined in the liquid phase using a fluorescence polarization assay.

An efficient and stereoselective method for the preparation of 4-amino(methyl)-1,3-thiazole-5-carboxylic acids starting from N-Fmoc-amino acids is reported.

A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) method for quantification of D-glucosamine-6P (GlcN-6P) that allows the kinetic study of glucosamine-6P synthase (Glms) is presented. The present report describes the optimization of the different steps of a new enzymatic assay for Glms based on in situ N-acetylation of GlcN-6P and MALDI-TOFMS analysis using N-(13C2)acetylglucosamine-6P as internal standard. Since no isotopically substituted GlcN-6P was available, the N-(13C2)acetyl derivative, easily obtained from (13C4)-acetic anhydride, was used as internal standard. Validation of the assay was achieved by measuring the fructose-6P Michaelis constant, in full agreement with reported values, and by studying the inhibition properties of arabinose-5P oxime.

International audience; The growing field of applications of O-alkyl hydroxylamines in medicinal chemistry and chemical biology has motivated the search for a parallel synthesis. A solid-phase approach based on the alkylation by alcohols of a new supported N-hydroxyphthalimide reagent using a Mitsunobu reaction followed by methylaminolysis has been optimized. This study points out the importance of the linker and a specific base effect for the Mitsunobu reaction. A large variety of alcohols can be used to give with moderate to high yields diverse O-alkyl hydroxylamines in high purity.

Ester (I), readily available from isoxazole in 3 steps, is transformed to the desired ring system (III) whose reactivity toward amines, thiols, alcohols, and amino acids is investigated.

The synthesis of optically pure heterocyclic scaffolds (V) (12 examples) is achieved through selective C-acylation of the aminoimidazopyridine (I) with various amino acids and subsequent intramolecular carbonylation.

Some new optically pure title compounds such as (VIII) and (XII) are prepared via selective C-3 acylation.

A tandem aza-Friedel–Crafts reaction/Hantzsch cyclization is described to access various polysubstituted 2-amino-1,3-thiazoles from electron-rich (hetero)-aromatic rings, aldehydes, thiourea and α-chloroketones.

International audience; Many protein-protein interactions involved in cell signalling, cell adhesion and regulation of transcription are mediated by short a-helical recognition motifs with the sequence Leu-Xaa-Xaa-Leu- Leu (LXXLL, where Xaa is any amino acid). Originally observed in cofactors that interact with hormone-activated nuclear receptors, LXXLL motifs are now known to occur in many transcription factors, including the STAT family, which transmit signals from activated cytokine receptors at the cell surface to target genes in the nucleus. STAT 6 becomes activated in response to IL-4 and IL-13, which regulate immune and anti-inflammatory responses. Structural studies have revealed how an LXXLL motif located in 2.5 turns of an a-helical peptide derived from STAT 6 provide contacts through the leucine side chains to the coactivator of transcription, NCoA-1. However, since many protein-protein interactions are mediated by LXXLL motifs, it is important to understand how specificity is achieved in this and other signalling pathways. Here, we show that energetically important contacts between STAT 6 and NCoA-1 are made in residues that flank the LXXLL motif, including the underlined residues in the sequence LLPPTEACHTUNGTRENUNGQDLTKLL. We also demonstrate how the affinity for NCoA-1 peptides derived from this region of STAT 6 can be significantly improved by optimising knobs-into-holes contacts on the surface of the protein. The results provide important new insights the origins of binding specificity, and might be of practical value in the design of novel small-molecule inhibitors of this important protein-protein interaction.