In 2021, novel oxylipins plasmodiophorol A-C were identified as products of the hydroperoxide bicyclase activity of CYP50918A1 from Plasmodiophora brassicae (Rhizaria, SAR). Here, we report the first total syntheses of plasmodiophorol A and C in 12 and 13 steps, respectively, starting from chiral tetrahydro-1H-cyclopentafuranone. Key transformations included enzymatic desymmetrization, epimerization, and diastereoselective Grignard addition. Notably, during the synthesis of plasmodiophorol C, we also generated and structurally characterized a previously unknown compound. These synthetic routes provide reliable access to plasmodiophorols A and C, offering valuable standards for probing their biosynthetic pathways and facilitating their identification in marine biomasses. This work lays the foundation for further chemical and biological studies of these unique oxylipins.

Propolis produced by honeybees, Apis mellifera, has been valued since ancient times as a remedy for different ailments for its broad medicinal properties. This wide range of biological activities may arise from the production of distinct propolis types within the hive, each serving specific functions and containing unique molecular compositions. In this study, we investigated the effects of four propolis types—masonry, sealing, brood-protection, and intruder-neutralizing—on hydrogen peroxide (H2O2)-induced oxidative injury in human skeletal muscle cells. Among these, only brood-protection propolis significantly prevented the H2O2-induced loss of cell viability. Bio-guided fractionation of this active propolis identified five major compounds: benzyl caffeate (BC), caffeic acid phenethyl ester (CAPE), cinnamyl caffeate (CC), prenyl caffeate (PC), and (E)-3-methyl-3-butenyl caffeate (MBC), all displaying stronger cytoprotective effects than their ferulate equivalents. We finally demonstrated that propolis extract and its active compounds reduced lipid peroxidation in post-mortem minced mouse skeletal muscle and compared their efficacy to other natural compounds. Chemical analysis of resins from neighboring flora suggested that black poplar (Populus nigra) buds are the primary botanical source of these caffeate derivatives. Collectively, these results highlight the functional diversity of hive propolis and its potential applications in food preservation as well as in complementary and preventive medicine.

Precise control of peptide backbone folding through non-covalent interactions remains a major challenge in foldamer design. In this work, we demonstrate that heteroatom substitutions program conformational switching in azole γ-peptides by tuning intrinsic stereoelectronic effects within heterocyclic γ-amino acids. Conformationally constrained thiazole- and oxazole-based γ-amino acids were designed to adopt conformations driven by either a C9 or a C7 intramolecular H-bond depending on key 1,4-X···O interactions (X = S or N). We previously showed that thiazole-based oligomers form a well-characterized canonical 9-Helix. Here, permutation of the sulfur and nitrogen atoms within the heterocycle induces a stretched helical structure with alternating C7-turns and residues in extended conformations. This unusual topology arises from competition between seven-membered intra-residue H-bonds and attractive S···N electrostatic-chalcogen interactions. Reversing this effect through an S→O substitution affords oxazole-derived oligomers that adopt a stable 7-Helix stabilized by a continuous seven-membered H-bond network in solution. These findings show that simple heteroatom permutation or substitution allows control over heterocyclic γ-peptide folding, thereby expanding opportunities for foldamer design in molecular recognition, catalysis, and biomedical applications.

The structural optimization of ATC‐based foldamer catalysts for the enantioselective nitro‐Michael addition of ketones to nitroolefins is reported. Building on the previous work with heteroaromatic γ‐peptides, the influence of the spatial arrangement and flexibility around the catalytic site is investigated. A series of modified sequences are designed to fine‐tune transition state preorganization while revisiting the contribution of an intramolecular proton donor function in ATC catalysts. These modifications lead to enhanced catalytic performance, with faster reaction rates and improved enantioselectivities under optimized conditions.

Peripheral nerve injury increasingly affects people around the world, leading to very incapacitating conditions with the loss of motor and sensory functions. Combining biomaterials with glial cells is particularly promising to reconnect injured axons to their original target, as they represent a supportive environment facilitating cell and axonal growth. Neural tissue engineering using biomimetic soft scaffolds often faces challenges related to handling, suturability, and integration into the host tissue. This study aimed to develop a soft and flexible biomimetic scaffold that supports colonization with a high density of glial Schwann cells (SCs). The strategy consists of printing tubular multichannel (500 to 1000 μm channels) nerve guides (NG) (5 × 5 mm) presenting an anisotropic architecture using a high-resolution stereolithography printing process. To this aim, the synthesis of photosensitive methacrylated gelatin (GelMA) inks was optimized and combined with various ratios of dimethacrylated F127 Pluronic. We showed that the physicochemical and mechanical properties of the printed hydrogels can be controlled by polymer concentrations and ratios. Specifically, in a 12:3 GelMA:F127DMA ratio, Pluronic provides enhanced flexibility while maintaining softness similar to nerve tissues. Importantly, gelatin-Pluronic scaffolds better withstand handling than gelatin scaffolds, as demonstrated by a higher strain at break in compression assays. Moreover, strain at break in suturing experiments was more than doubled with GelMA:F127DMA (35%) hydrogels in contrast to fragile and brittle gelatin-only scaffolds (15%). Schwann cells adhere, proliferate, and remain viable over 7 days within the channels demonstrating that these cellularized gelatin-Pluronic nerve guides hold significant promise for nerve regeneration.

Various series of 4,6-disubstituted-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Altogether, about ninety compounds were prepared using a general synthetic pathway involving one or two steps (eventually one-pot) procedures. Variation of the nature of the substituents in positions 4 and 6 (methyl, trifluoromethyl or phenyl) of the thiopurine ring, as well as on the thiol function, was examined and led to marked differences both in term of reactivity and ability to interfere with the putative target protein. Using a functional assay on immune cells, few compounds belonging to series 4 were shown to be able to antagonize the inhibition of the T-cell proliferation at both 100 mu M and 10 mu M (completely for 4 ab and partially for 4 ai), that is as potent as AOPCP which entirely reversed the inhibitory impact of exogenous ATP on T cell proliferation until 62.5 mu M. In addition, we have shown that both compounds (4 ab and 4 ai) were also capable of moderately inhibiting the hA2A receptor with Ki in the mu molar range in HEK-293 cells. Thus, with the aim to reduce the molecular size and the lipophilicity of our initial scaffold, we finally observed by serendipity a modification of the potential target of our compounds.

With aging, harsh working conditions or sports injuries, the meniscus can degrade, causing pains to the patient. Nowadays, the treatment consists of the surgical replacement of this cartilage. Since this procedure can lead to complications due to open wounds and potential infections, synthesizing a polyurethane-based injectable joint filler represents an interesting alternative. In this study, poly(δ-decalactone)triol oligomers and Lysine diisocyanate were chosen as starting monomers to create an isocyanate-based prepolymer, because of their biocompatibility and liquid state at room temperature. Nevertheless, to fully replace the meniscus, the joint filler must crosslink in vivo, and this should occur in a short time window. Accordingly, in this work, we studied the catalytic activity of a range of relatively safe compounds for the alcohol/isocyanate addition reaction. A preliminary 1H NMR kinetic study of the catalyzed addition of 1-butanol or 3-pentanol on lysine diisocyanate ethyl ester at body temperature has been performed to reach this objective. Among catalysts, stannous octoate was the most effective with either primary or secondary alcohol, allowing them to reach 92 and 80% alcohol conversion, respectively. In addition, the conversion of the primary and secondary isocyanates of lysine diisocyanate ethyl ester was monitored for all the catalysts and revealed different behaviors depending on the catalyst employed. Stannous octoate, unlike the others, showed a similar reactivity for primary and secondary isocyanates with conversions of 49 and 47%, respectively. Finally, when employing the most effective catalyst, curing of the poly(δ-decalactone) triisocyanate with glycerol at 35 °C provided a polyurethane elastomer that exhibits an elastic modulus of 519 kPa and a swelling index lower than 3% in PBS, making it suitable for injectable polyurethane joint filler application.

The chemistry of chitosan is a promising way to afford biobased and biodegradable complex materials using highly reactive compounds such as anhydrides. However, the potential applications are limited due to the absence of control over the acylation and the lack of precise characterization. After a model study on glucosamine, a selective acylation method of amines or alcohols of chitosan oligomers using anhydrides has been developed. The N-acylation of chitooligosaccharides has been achieved using several anhydrides and the O-acylation has been achieved in three steps: (1) Amine protection using p-anisaldehyde (2) O-acylation (with four anhydrides), and (3) Amine deprotection by removing the protective anisyl groups. Functionalized chitooligosaccharides have been characterized by a precise quantification method using 13C nuclear magnetic resonance spectroscopy. The resulting degrees of substitution show in most of the cases a stochiometric reaction between anhydrides and amines of chitooligosaccharides, and around 70% of efficiency for O-acylation, proving the promising potential of such modifications. To the best of our knowledge, we describe here the first example of selective acylation of chitooligosaccharides using anhydrides, and most of all the first example of 13C quantitative NMR spectroscopy performed on chitooligosaccharides and its derivatives. These innovative structures are the gateway to the creation of new biosourced and/or biodegradable surfactants.

Hybrid organic-inorganic bio-inspired apatite nanoparticles (NPs) are attractive for biomedical applications and especially in nanomedicine. Unfortunately, their applications in nanomedicine are limited by their broad particle size distributions and uncontrolled drug loading due to their multistep synthesis process.  Besides, very few attempts at exposing bioactive peptides on apatite NPs are made. In this work, an original one-pot synthesis of well-defined bioactive hybrid NPs composed of a mineral core of bioinspired apatite surrounded by an organic corona of bioactive peptides is reported. Dual stabilizing-bioactive agents, phosphonated polyethylene glycol-peptide conjugates, are prepared and directly used during apatite precipitation i) to form the organic corona during apatite precipitation, driving the size and shape of resulting hybrid NPs with colloidal stabilization and ii) to expose peptide moieties (RGD or YIGSR sequences) at the NPs periphery in view of conferring additional surface properties to enhance their interaction with cells. Here, the success of this approach is demonstrated, the functionalized NPs are fully characterized by Fourier-transform infrared, Raman, X-ray diffraction, solid and liquid state NMR, transmission electron microscopy, and dynamic light scattering, and their interaction with fibroblast cells is followed, unveiling a synergistic proliferative effect.

Shape memory polyurethane (SMPU) have the capacity to alter and regain their form in reaction to a stimulus (eg. temperature, pH) and have been investigated in biomedical applications. In this work, the shape memory properties of poly(ester-urethane)s (PEU) are studied as a function of the functionality of the poly(lactide-coglycolide) (PLGA) and poly(e-caprolactone) (PCL) pre-polymers. Two distinct series of PEU are synthesized by reaction between linear and star-shaped PLGA polyols initiated by pentaerythritol (4-arms PLGA) or dipentaerythritol (6-arms PLGA) with PCL di-isocyanate prepolymers. The different PEUs exhibit thermally actuated shape memory properties and tunable mechanical properties with Young's moduli reaching up to 96 MPa and elongation at break reaching 930 %. The integration of low amounts of PLGA star within the PEU structure increases the material's shape memory properties, enhancing both fixity (from 45 % to 96 %) and recovery ratios (from 88 % to 92 %). Further exploration into potential applications led to the formulation of porous foams via the solvent casting/particles leaching (SC/PL) process. These foams exhibited high porosity ranging from 74 % to 83 % with pore sizes spanning from 100 to 300 mu m. Their mechanical properties are close to the human meniscus with Young's modulus ranging from 0.13 MPa to 0.53 MPa. Moreover, integration of PLGA star within the PEU scaffold decreases the flexural strength that is an important parameter for potential mini-invasive surgery.

Due to growing concerns about environmental issues and the decline of petroleum-based resources, the synthesis of new biobased compounds for the polymer industry has become a prominent and timely topic. P-menthane-1,8-diamine (PMDA) is a readily available compound synthesized from turpentine, a cheap mixture of natural compounds isolated from pine trees. PMDA has been extensively used for its biological activities, but it can also serve as a source of valuable monomers for the polymer industry. In this work, commercial PMDA (ca. 85% pure) was purified by salinization, crystallization, and alkali treatment and then converted into p-menthane-1,8-diisocyanate (PMDI) through a phosgene-free synthesis at room temperature. A thorough analytical study using NMR techniques (1H, 13C, 13C-1H HSQC, 13C-1H HMBC, and 1H-1H NOESY) enables the characterization of the cis-trans isomeric mixtures of both PMDA and PMDI. These structural studies allowed for a better understanding of the spatial configuration of both isomers. Then, the reactivity of PMDI with a primary alcohol (benzyl alcohol) was studied in the presence of nine different catalysts exhibiting different activation modes. Finally, the use of PMDI in the synthesis of polyurethanes was explored to demonstrate that PMDI can be employed as a new biobased alternative to petrochemical-based isocyanates such as isophorone diisocyanate (IPDI).

The chemistry of chitosan is a promising way to afford biobased and biodegradable complex materials using highly reactive compounds such as anhydrides. However, the potential applications are limited due to the absence of control over the acylation and the lack of precise characterization. After model study on glucosamine, a selective acylation method of amines or alcohols of chitosan oligomers using anhydrides has been developed. The N-acylation of COS has been achieved using several anhydrides and the O-acylation has been realized in three steps: (1) Amine protection using p-anisaldehyde (2) O-acylation (with four anhydrides), and (3) Amine deprotection by removing the protective anisyl groups. Functionalized COS have been characterized by a precise quantification method using 13C Nuclear Magnetic Resonance (NMR) spectroscopy. The resulting degrees of substitution show in most of the case a stochiometric reaction between anhydrides and amines of COS, and around 70% of efficiency for O-acylation, proving the promising potential of such modifications. To the best of our knowledge, we describe here the first example of selective acylation of COS using anhydrides, and most of all the first example of 13C quantitative NMR spectroscopy performed on COS and its derivatives.

17O NMR spectroscopy is a powerful analytical technique, which enables to access unique information regarding the structure and reactivity of biomolecules, such as peptides and proteins. However, due to the exceedingly low natural abundance of 17O (0.04 %), it is necessary to work with 17O-enriched samples, which are not easily accessible because of the experimental constraints and high costs associated with the traditional enrichment procedures. Here, we present simple, fast and cost-efficient labeling strategies for 17O-enrichment of amino acids and peptides. First, using mechanochemical saponification, a variety of unprotected amino acids were enriched within 30 min of milling under ambient conditions, consuming only microliter amounts of costly labeled water, and producing pure molecules with high enrichment levels (up to ~ 40 %), and in medium to high yields (~ 60 - 85 %) without the loss of their optical purity (ee > 99%). The labeling efficiency of the mechanochemical protocol was then compared to a re-optimised enrichment strategy based on acid-catalysed oxygen exchange. Subsequently, 17O-enriched Fmoc/tBu-protected amino acids were produced on a 1 g/day scale with high enrichment levels (~ 40 %), and in high synthetic yields (~ 75 - 85 %), by scaling up the mechanochemical enrichment followed by a Fmoc-protection step. Lastly, a direct site-selective 17O-labeling of carboxylic functions in peptide side-chains was developed and applied to the RGD and GRGDS peptides, reaching up to 29% enrichment level. Producing highly enriched molecules enabled to record 17O solid-state NMR spectra at 14.1 T in reasonable analytical times. Overall, this work represents an important step forward in providing easy access to highly 17O-enriched peptides and proteins to be subsequently studied by high-resolution 17O NMR spectroscopy.

Dynamic covalent polymers (DCPs) offer opportunities as adaptive materials of particular interest for targeting, sensing and delivery of biological molecules. In this view, combining cationic units and fluorescent units along DCP chains is attractive for achieving optical probes for the recognition and delivery of nucleic acids. Here, we report on the design of acylhydrazone-based DCPs combining cationic arginine units with π-conjugated fluorescent moieties based on thiophene-ethynyl-fluorene cores. Two types of fluorescent building blocks bearing neutral or cationic side groups on the fluorene moiety are considered in order to assess the role of the number of cationic units on complexation with DNA. The (chir)optical properties of the building blocks, the DCPs, and their complexes with several types of DNA are explored, providing details on the formation of supramolecular complexes and on their stability in aqueous solutions. The DNA-templated formation of DCPs is demonstrated, which provides new perspectives on the assembly of fluorescent DCP based on the nucleic acid structure.

The voltage-dependent anion channel (VDAC), the most abundant protein on the outer mitochondrial membrane, is implicated in ATP, ion and metabolite exchange with cell compartments. In particular, the VDAC participates in cytoplasmic and mitochondrial Ca2+ homeostasis. Notably, the Ca2+ efflux out of Schwann cell mitochondria is involved in peripheral nerve demyelination that underlies most peripheral neuropathies. Hexokinase (HK) isoforms I and II, the main ligands of the VDAC, possess a hydrophobic N-terminal structured in α-helix (NHKI) that is necessary for the binding to the VDAC. To gain further insight into the molecular basis of HK binding to the VDAC, we developed and optimized peptides based on the NHKI sequence. These modifications lead to an increase of the peptide hydrophobicity and helical content that enhanced their ability to prevent peripheral nerve demyelination. Our results provide new insights into the molecular basis of VDAC/HK interaction that could lead to the development of therapeutic compounds for demyelinating peripheral neuropathies.

Four porphyrins equipped with imidazolium rings on the para positions of their meso aryl groups were prepared and used as tetrakis(N-heterocyclic carbene) (NHC) precursors for the synthesis of porphyrin cages assembled from eight NHC-M bonds (M = Ag+ or Au+). The conformation of the obtained porphyrin cages in solution and their encapsulation properties strongly depend on the structure of the spacer -(CH2)(n)- (n = 0 or 1) between meso aryl groups and peripheral NHC ligands. In the absence of methylene groups (n = 0), porphyrin cages are rather rigid and the short porphyrin-porphyrin distance prevents the encapsulation of guest molecules like 1,4-diazabicyclo[2.2.2]octane (DABCO). By contrast, the presence of methylene functions (n = 1) between meso aryl groups and peripheral NHCs offers additional flexibility to the system, allowing the inner space between the two porphyrins to expand enough to encapsulate guest molecules like water molecules or DABCO. The peripheral NHC-wingtip groups also play a significant role in the encapsulation properties of the porphyrin cages.

The aim of our study was to identify novel molecules able to induce an adaptative response against oxidative stress during the first stages of metabolic syndrome. A cellular survival in vitro test against H2O2-based test was applied after pretreatment with various natural bitter Asteraceae extracts. This screening revealed potent protection from burdock leaf extract. Using chromatography and LC-MS—RMN, we then isolated and identified an original sesquiterpene lactone bioactive molecule: the Xanthatin-13-(pyrrolidine-2-carboxylic acid) (XPc). A real-time RT-qPCR experiment was carried out on three essential genes involved in oxidative stress protection: GPx, SOD, and G6PD. In presence of XPc, an over-expression of the G6PD gene was recorded, whereas no modification of the two others genes could be observed. A biochemical docking approach demonstrated that XPc had a high probability to directly interact with G6PD at different positions. One of the most probable docking sites corresponds precisely to the binding site of AG1, known to stabilize the G6PD dimeric form and enhance its activity. In conclusion, this novel sesquiterpene lactone XPc might be a promising prophylactic bioactive agent against oxidative stress and inflammation in chronic diseases such as metabolic syndrome or type 2 diabetes.

Two mechanochemical procedures for 17O/18O-isotope labeling of fatty acids are reported: a carboxylic acid activation/hydrolysis approach and a saponification approach.

While artificial cyclases hold great promise in chemical synthesis, this work presents the first example of a DNA-catalyzed inverse electron-demand hetero-Diels-Alder (IEDHDA) between dihydrofuran and various α,β-unsaturated acyl imidazoles. The resulting fused bicyclic O,O-acetals containing three contiguous stereogenic centers are obtained in high yields (up to 99 %) and excellent diastereo- (up to >99:1 dr) and enantioselectivities (up to 95 % ee) using a low catalyst loading. Most importantly, these results show that the concept of DNA-based asymmetric catalysis can be expanded to new synthetic transformations offering an efficient, sustainable, and highly selective tool for the construction of chiral building blocks.

Fatty acids are ubiquitous in biological systems and widely used in materials science, including for the formulation of drugs and the surface-functionalization of nanoparticles. However, important questions regarding the structure and reactivity of these molecules are still to be elucidated, including their mode of binding to certain metal cations or materials surfaces. In this context, we have developed novel, efficient, user-friendly, and cost-effective synthetic protocols based on ball-milling, for the 17O and 18O isotopic labeling of two key fatty acids which are widely used in (nano)materials science, namely stearic and oleic acid. Labeled molecules were analyzed by 1H and 13C solution NMR, IR spectroscopy, and mass spectrometry (ESI-TOF and LC-MS), as well as 17O solid state NMR (for the 17O labeled species). In both cases, the labeling procedures were scaled-up to produce up to gram quantities of 17O- or 18O-enriched molecules in just half-a-day, with very good synthetic yields (all ≥84%) and enrichment levels (up to an average of 46% per carboxylic oxygen). The 17O-labeled oleic acid was then used for the synthesis of a metal soap (Zn-oleate) and the surface-functionalization of ZnO nanoparticles (NPs), which were characterized for the first time by high-resolution 17O NMR (at 14.1 and 35.2 T). This allowed very detailed insight into (i) the coordination mode of the oleate ligand in Zn-oleate to be achieved (including information on Zn···O distances) and (ii) the mode of attachment of oleic-acid at the surface of ZnO (including novel information on its photoreactivity upon UV-irradiation). Overall, this work demonstrates the high interest of these fatty acid-enrichment protocols for understanding the structure and reactivity of a variety of functional (nano)materials systems using high resolution analyses like 17O NMR.