New Selective Inhibitors of α-Glucosidase for the Treatment of Type 2 Diabetes Mellitus
Khanchouch, T.; Vallin, A.; Alali, U.; Benazza, M.; Abidi, R.; Bonnet, V.
Helv. Chim. Acta n/a, e202300222.
Abstract Type 2 diabetes mellitus is a metabolic dreadful disease caused by an uncontrolled glucose level in the bloodstream, particularly high after a meal. Inhibitors of glucosidases, involved in the digestion of carbohydrates, can regulate this post-prandial increase in glucose concentration. The traditional drugs act as competitive inhibitors of both pancreatic α-amylase and α-glucosidases and this unselective inhibition is behind severe gastrointestinal side effects related to the concomitant inhibition of α-amylase. We described herein some perglycosylated cyclodextrins as efficient and selective inhibitors of α-glucosidase with low micromolar IC50 (3.64-7.98 μM) compared to the acarbose (IC50 212 μM), clinically used for patients suffering from type 2 diabetes. On the other hand, they do not inhibit α-amylase (IC50>500 μM). Structure/activity relationship rationalization suggests multiple interactions between the described inhibitors and α-glucosidase, which support the existence of both active site and allosteric interactions.
https://dx.doi.org/10.1002/hlca.202300222

Ion mobility mass spectrometry enables the discrimination of positional isomers and the detection of conformers from cyclic oligosaccharides-metals supramolecular complexes
Bonnet, V.; Clodic, G.; Sonnendecker, C.; Zimmermann, W.; Przybylski, C.
Carbohydr. Polym. 2023, 320, 121205.
Cyclic oligosaccharides are well known to interact with various metals, able to form supramolecular complexes with distinct sizes and shapes. However, the presence of various isomers in a sample, including positional isomers and conformers, can significantly impact molecular recognition, encapsulation ability and chemical reactivity. Therefore, it is crucial to have tools for deep samples probing and correlation establishments. The emerging ion mobility mass spectrometry (IM-MS) has the advantages to be rapid and sensitive, but is still in its infancy for the investigation of supramolecular assemblies. In the herein study, it was demonstrated that IM-MS is suitable to discriminate several isomers of cyclodextrins (CD)-metals complexes, used as cyclic oligosaccharide models. In this sense, we investigated branched 6-O-α-glucosyl- or 6-O-α-maltosyl-β-cyclodextrins (G1-β-CD and G2-β-CD) and their purely cyclic isomers: CD8 (γ-CD) and CD9 (δ-CD). The corresponding collision cross section (CCS) values were deducted for the main positive singly and doubly charged species. Experimental CCS values were matched with models obtained from molecular modelling. The high mobility resolving power and resolution enabled discrimination of positional isomers, identification of various conformers and accurate relative content estimation. These results represent a milestone in the identification of carbohydrate conformers that cannot be easily reached by other approaches.
https://dx.doi.org/10.1016/j.carbpol.2023.121205

Enzymatically demethylated pectins: from fruit waste to an outstanding polymer binder for silicon-based anodes of Li-ion batteries
Ndour, M.; Bonnet, J.-P.; Cavalaglio, S.; Lombard, T.; Safran, J.; Pau-Roblot, C.; Bonnet, V.
New J. Chem. 2023, 47, 17499-17507.
Pectin is a polysaccharide frequently found in large amounts in the peel and seeds of many fruits and therefore represents very common food industry waste. In this study, we investigate demethylated citrus and apple pectins with a methylation degree ranging from 76% to 3%, as polymer binders for silicon-based anodes of lithium-ion batteries. Both chemical and enzymatic pectin demethylations were considered. First, the usual aggressive saponification reaction was carried out leading to 24% and 28% methylesterified pectins from citrus and apple, respectively, but leading at the same time to unavoidable strong pectin depolymerization, as shown by SEC studies. In a second approach, the methylesterase enzyme was used to catalyze citrus pectin demethylation leading to a similar methylesterification degree (24%) but drastically minimizing polymer chain degradation. Our best-demethylated pectin was compared with the standard polymer binder for Li-ion batteries i.e. carboxymethyl cellulose (CMC) inside a composite silicon anode for their effect on silicon electrochemical capacity retention. The 24% enzymatically demethylated citrus pectin achieved here a remarkable capacity of 2275 mA h g−1 after 49 cycles with a load of 1.6 mg cm−2 compared to 245 mA h g−1 measured for CMC. These demethylated pectins have a buffering effect on the silicon particles’ volume change during discharge/charge cycles. The increase of interactions between silicon and pectin, probably due to the presence of numerous carboxylic acid functions in this demethylated pectin, is hypothesized to be, at least partly, responsible for these enhanced electrochemical performances. In addition, the existing type of glycosidic linkage (α in pectins and β in CMC) can also be responsible for these enhanced results.
https://dx.doi.org/10.1039/D3NJ02736H

Fragmentation of DMPC Membranes by a Wedge-Shaped Amphiphilic Cyclodextrin into Bicellar-like Aggregates
Roux, M.; Legrand, F. X.; Bil, A.; Bonnet, V.; Djedaini-Pilard, F.
J. Phys. Chem. B 2023.
Small bilayer lipid aggregates such as bicelles provide useful isotropic or anisotropic membrane mimetics for structural studies of biological membranes. We have shown previously by deuterium NMR that a wedge-shaped amphiphilic derivative of trimethyl betacyclodextrin anchored in deuterated DMPC-d27 bilayers through a lauryl acyl chain (TrimbetaMLC) is able to induce magnetic orientation and fragmentation of the multilamellar membranes. The fragmentation process fully detailed in the present paper is observed with 20% cyclodextrin derivative below 37 degrees C, where pure TrimbetaMLC self-assembles in water into large giant micellar structures. After deconvolution of a broad composite (2)H NMR isotropic component, we propose a model where the DMPC membranes are progressively disrupted by TrimbetaMLC into small and large micellar aggregates depending whether they are extracted from the outer or inner layers of the liposomes. Below the fluid-to-gel transition of pure DMPC-d27 membranes (T(c) = 21.5 degrees C), the micellar aggregates vanish progressively until complete extinction at 13 degrees C, with a probable release of pure TrimbetaMLC micelles leaving lipid bilayers in the gel phase doped with only a small amount of the cyclodextrin derivative. Bilayer fragmentation between T(c) and 13 degrees C was also observed with 10% and 5% of TrimbetaMLC, with NMR spectra suggesting possible interactions of micellar aggregates with fluid-like lipids of the P(beta') ripple phase. No membrane orientation and fragmentation was detected with unsaturated POPC membranes, which are able to accommodate the insertion of TrimbetaMLC without important perturbation. The data are discussed in relation to the formation of possible DMPC bicellar aggregates such as those known to occur after insertion of dihexanoylphosphatidylcholine (DHPC). These bicelles are in particular associated with similar deuterium NMR spectra exhibiting identical composite isotropic components which were never characterized before.
https://dx.doi.org/10.1021/acs.jpcb.2c07331

The formulation of a CMC binder/silicon composite anode for Li-ion batteries: from molecular effects of ball milling on polymer chains to consequences on electrochemical performances
Ndour, M.; Bonnet, J.-P.; Cavalaglio, S.; Lombard, T.; Courty, M.; Aymard, L.; Przybylski, C.; Bonnet, V.
Materials Advances 2022.
The semi-synthetic polysaccharide carboxymethylcellulose (CMC) is one of the most studied and effective polymer binders for silicon-based anodes in Li-ion batteries. The formulation of the corresponding composite negative electrode with an appropriate mixture of electroactive silicon, a CMC binder and a carbon additive is mandatory to ensure a good electrical conductivity. Blending is commonly realized by a highly energetic ball milling treatment of these three aforementioned components. This type of mixing reduces the size of the obtained particles and can also potentially agglomerate them. Morever, it allows the formation of a nanostructured mixture which is essential for both the silicon activation and to achieve good electrochemical performance. However, such strong treatment can also cause a significant degradation of the polymer chains, as we have recently demonstrated for polyacrylic acid (PAA). In the present work, the structural and chemical effects of this mechanical grinding on three commercial CMCs ranging from 90 to 700 kg mol−1 were investigated. All the polymers were characterized using SEC-MALLS, FTIR spectroscopy, MALDI-TOF mass spectrometry and TGA-MS thermal analysis. In all cases, a huge average molecular weight decrease was noticed, leading to the appearance of a bimodal distribution with low (52–72 kg mol−1) to very low molecular weight populations (1–1.8 kg mol−1). From these results, two formulations of a negative electrode were compared, one with ball milling of the three compounds and another one including only ball milling steps for silicon and carbon. After the correlation of the characteristics of this negative electrode composite with the electrochemical results, it was demonstrated that a high number of functions for supramolecular or covalent linkages are keypoints of the herein anode performance. Low molecular weight CMC derivatives (about 64 kg mol−1) obtained by ball milling treatment led to higher stability of the electrode.
https://dx.doi.org/10.1039/D2MA00702A

Probing topology of supramolecular complexes between cyclodextrins and alkali metals by ion mobility-mass spectrometry
Przybylski, C.; Bonnet, V.
Carbohydr. Polym. 2022, 297, 120019.
In this study, the size and shape of supramolecular assemblies between cyclo-oligosaccharides and proton, ammonium or a series of alkali metals by electrospray coupled to trapped ion mobility-mass spectrometry (ESI-TIMS) have investigated. Native cyclodextrins (CD) were selected as models, and collision cross section (CCS) values were deducted for the main positive singly and doubly charged species. Experimental CCS values were in good agreement with those obtained from molecular modeling. Due to the high mobility resolving power and resolution, it was possible to highlight the presence of various conformers. Also, TIMS allowed to discriminate and estimate the content of various orientations from non-covalent nanotubes-based CD, involving secondary/secondary rim hydroxyl groups (head-to head), primary/secondary rim (head-to-tail) hydroxyl groups or primary/primary rim (tail-to-tail) hydroxyl groups interactions. Such results pave the way for a better knowledge of the topology of cyclo-oligosaccharides based supramolecular complexes, demonstrating that TIMS can be a particularly attractive molecular descriptor.
https://doi.org/10.1016/j.carbpol.2022.120019

Ring-Opening of Cyclodextrins: An Efficient Route to Pure Maltohexa-, Hepta-, and Octaoses
Pélingre, M.; Koffi Teki, D. S.-E.; El-Abid, J.; Chagnault, V.; Kovensky, J.; Bonnet, V.
Organics 2021, 2, 287-305.
Many preparations of maltooligosaccharides have been described in literature, essentially using enzymatic or biotechnological processes. These compounds, derived from starch, are well-known as prebiotic agents. The use of maltohexa-, hepta-, and octaoses as synthons in organic synthesis was also well documented in literature. They can indeed be obtained as single compounds by the cyclodextrins’ ring-opening. This reaction has been studied for many years, varying the protecting and functional groups and the reaction conditions, leading to functionalized oligomaltoses. These compounds are of wide interest in various fields. They have a strong potential as scaffolds for multivalence in chemobiology, as building blocks for the production of biomimetic pseudo-glycopeptides, as well as monomers for the preparation of materials. In view of the importance of these oligomaltoses, this review focuses on the different methodologies allowing access to them via chemical and enzymatic ring-opening of cyclodextrins.
https://dx.doi.org/10.3390/org2030015

One-Pot Synthesis of Asymmetrically Difunctionalized Oligomaltosides by Cyclodextrin Ring Opening
Pélingre, M.; Smadhi, M.; Bil, A.; Bonnet, V.; Kovensky, J.
ChemistryOpen 2021, 10, 493-496.
Abstract The synthesis of pure difunctionalized hexa-, hepta- and octamaltosides was performed by one-pot chemical reaction from perbenzoylated cyclodextrin. Oligomaltosides with azide, propargyl or allyl on reducing end and an unprotected hydroxyl group on non-reducing end were obtained from perbenzoylated α-, β- and γ-cyclodextrin with 12 to 48 % yields.
https://doi.org/10.1002/open.202100079

First Steps to Rationalize Host–Guest Interaction between α-, β-, and γ-Cyclodextrin and Divalent First-Row Transition and Post-transition Metals (Subgroups VIIB, VIIIB, and IIB)
Dossmann, H.; Fontaine, L.; Weisgerber, T.; Bonnet, V.; Monflier, E.; Ponchel, A.; Przybylski, C.
Inorg. Chem. 2021, 60, 930-943.
Cyclodextrins (CDs) are cyclic oligosaccharides mainly composed of six, seven, and eight glucose units, so-called α-, β-, and γ-CDs, respectively. They own a very particular molecular structure exhibiting hydrophilic features thanks to primary and secondary rims and delimiting a hydrophobic internal cavity. The latter can encapsulate organic compounds, but the former can form supramolecular complexes by hydrogen-bonding or electrostatic interactions. CDs have been used in catalytic processes to increase mass transfer in aqueous–organic two-phase systems or to prepare catalysts. In the last case, interaction between CDs and metal salts was considered to be a key point in obtaining highly active catalysts. Up to now, no work was reported on the investigation of factors affecting the binding of metal to CD. In the study herein, we present the favorable combination of electrospray ionization coupled to mass spectrometry [ESI-MS(/MS)] and density functional theory molecular modeling [B3LYP/Def2-SV(P)] to delineate some determinants governing the coordination of first-row divalent transition metals (Mn2+, Co2+, Ni2+, Cu2+, and Fe2+) and one post-transition metal (Zn2+) with α-, β-, and γ-CDs. A large set of features concerning the metal itself (ionic radius, electron configuration, and spin state) as well as the complexes formed (the most stable conformer, relative abundance in MS, CE50 value in MS/MS, binding energy, effective coordination number, average bond lengths, binding site localization, bond dissociation energies, and natural bond orbital distribution) were screened. Taking into account all of these properties, various selectivity rankings have been delineated, portraying differential association/dissociation behaviors. Nonetheless, unique 3D topologies for each CD–metal complex were emphasized. The combination of these approaches brings a stone for building a compendium of molecular features to serve as a suitable descriptor or predictor for a better first round rationalization of catalytic activities.
https://dx.doi.org/10.1021/acs.inorgchem.0c03052

Discrimination of isomeric trisaccharides and their relative quantification in honeys using trapped ion mobility spectrometry
Przybylski, C.; Bonnet, V.
Food Chem. 2021, 341, 128182.
Carbohydrates play a myriad of critical roles as key intermediaries for energy storage, cell wall constituents, or also fuel for organisms. The deciphering of multiple structural isomers based on the monosaccharides composition (stereoisomers), the type of glycosidic linkages (connectivity) and the anomeric configuration (α and β), remains a major analytical challenging task. The possibility to discriminate 13 underivatized isomeric trisaccharides were reported using electrospray ionization coupled to trapped ion mobility spectrometry (ESI-TIMS). After optimization of scan ratio enhancing both the mobility resolving power (R) and resolution (r), fingerprints from 5 different honeys were obtained. Seven trisaccharides with relative content varying from 1.5 to 58.3%, were identified. It was demonstrated that their relative content and/or their ratio could be used to ascertain origin of the honeys. Moreover, such direct approach constitutes an alternative tool to current longer chromatographic runs, paving the way to a transfer as suitable routine analysis.
https://dx.doi.org/10.1016/j.foodchem.2020.128182

First step to the improvement of the blood brain barrier passage of atazanavir encapsulated in sustainable bioorganic vesicles
Nolay, F.; Sevin, E.; Létévé, M.; Bil, A.; Gosselet, F.; El Kirat, K.; Djedaini-Pilard, F.; Morandat, S.; Fenart, L.; Przybylski, C.; Bonnet, V.
Int. J. Pharm. 2020, 587, 119604.
The blood - brain barrier (BBB) prevents the majority of therapeutic drugs from reaching the brain following intravenous or oral administration. In this context, polymer nanoparticles are a promising alternative to bypass the BBB and carry drugs to brain cells. Amphiphilic cyclodextrins can form self-assemblies whose nanoparticles have a 100-nm-diameter range and are thus able to encapsulate drugs for controlled release. Our goal is to propose an optimized chemical synthesis of amphiphilic cyclodextrin, which remains a challenging task which commonly leads to only a low-milligram level of the high purity compound. Such cyclodextrin derivatives were used to prepare vesicles and to study their ability to vectorize a drug through the BBB. As a result, we introduced a convergent synthesis for a family of lipophosphoramidyl permethylated β-CDs (Lip-β-CDs) with various chain lengths. It was demonstrated that mixed vesicles comprised of phosphatidylcholine (POPC) and LipCDs were able to encapsulate atazanavir (ATV), a well-known protease inhibitor used as an antiretroviral drug against HIV. We highlighted that neo-vesicles promote the penetration of ATV in endothelial cells of the BBB, presumably due to the low fusogenicity of Lip-β-CDs.
https://dx.doi.org/10.1016/j.ijpharm.2020.119604

New Lipidyl-Cyclodextrins Obtained by Ring Opening of Methyl Oleate Epoxide Using Ball Milling
Oliva, E.; Mathiron, D.; Rigaud, S.; Monflier, E.; Sevin, E.; Bricout, H.; Tilloy, S.; Gosselet, F.; Fenart, L.; Bonnet, V.; Pilard, S.; Djedaini-Pilard, F.
Biomolecules 2020, 10, 339.
Bearing grafts based on fatty esters derivatives, lipidyl-cyclodextrins (L-CDs) are compounds able to form water-soluble nano-objects. In this context, bicatenary biobased lipidic-cyclodextrins of low DS were easily synthesized from a fatty ester epoxide by means of alternative methods (ball-milling conditions, use of enzymes). The ring opening reaction of methyl oleate epoxide needs ball-milling and is highly specific of cyclodextrins in solventless conditions. L-CDs are thus composed of complex mixtures that were deciphered by an extensive structural analysis using mainly mass spectrometry and NMR spectroscopy. In addition, as part of their potential use as vectors of active drugs, these products were submitted to an integrity study on in vitro model of the blood-brain-barrier (BBB) and the intestinal epithelium. No toxicity has been observed, suggesting that applications for the vectorization of active ingredients can be expected.
https://dx.doi.org/10.3390/biom10020339

Ordering of Saturated and Unsaturated Lipid Membranes near Their Phase Transitions Induced by an Amphiphilic Cyclodextrin and Cholesterol
Roux, M.; Bonnet, V.; Djedaïni-Pilard, F.
Langmuir 2019.
When inserted in membranes of dimyristoyl phosphatidylcholine (DMPC), methylated β-cyclodextrins with one (TrimβMLC) or two (TrimβDLC) lauryl acyl chains grafted onto the hydrophilic cavity exert a “cholesterol-like ordering effect”, by straightening the acyl chains in the fluid phase at temperatures near the chain melting transition. This effect may be related to pretransitional events such as the “anomalous swelling” known to occur with saturated phosphatidylcholine membranes. To investigate this model, order profiles and bilayer thicknesses of DMPC and unsaturated 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) membranes containing amphiphilic cyclodextrins or cholesterol were determined by deuterium NMR. The pure lipid membranes display both a qualitatively similar chain ordering upon cooling in the fluid phase, more important at the chain extremity, which gets more pronounced near their fluid-to-gel transitions. Both membranes show a bilayer thickness increase by ∼0.5 Å just above their transition, as observed previously with saturated phosphatidylcholines of various chain lengths. Membrane-insertion of 5% TrimβMLC or cholesterol induces an important ordering of the DMPC acyl chains just above the transition, which is also more pronounced at the chain extremity. There is an additional increase of the bilayer thickness, most probably due to a deep insertion of these amphiphilic molecules, facilitated by increased bilayer softness in the anomalous swelling regime. These effects are more important with TrimβMLC than with cholesterol. By contrast, no enhanced acyl chain ordering was observed when approaching the transition of TrimβMLC-containing POPC membranes, as a possible consequence of an eventual lack of anomalous swelling in unsaturated lipid membranes. Insertion of higher concentrations of TrimβMLC was found to induce a magnetic orientation of the DMPC membranes in the fluid phase with 10% of this derivative, coupled with the appearance of a broad isotropic component when the concentration is raised to 20%. No membrane orientation or isotropic component was detected with TrimβMLC-containing POPC membranes.
https://dx.doi.org/10.1021/acs.langmuir.9b02082

Highly Water-Soluble Amphiphilic Cyclodextrins Bearing Branched and Cyclic Oleic Grafts
Cocq, A.; Rousseau, C.; Bricout, H.; Oliva, E.; Bonnet, V.; Djedaïni-Pilard, F.; Monflier, E.; Tilloy, S.
Eur. J. Org. Chem.
Amphiphilic β-cyclodextrins bearing various amounts of branched and cyclic oleic grafts are synthetized. The first step of this synthesis is the alkenylation of maleic anhydride by oleic acid derivatives, in the presence of a rhodium catalyst, to produce oleic succinic anhydrides with different ratios of cyclic to branched groups. The second step is the grafting of the oleic succinic anhydrides mixtures on β-cyclodextrin. The obtained cyclodextrins are highly water-soluble and surface active.
https://dx.doi.org/10.1002/ejoc.201900789

Uncommon Strong Inhibition of α-Glucosidase by Multivalent Glycoclusters built on Cyclodextrins Scaffolds
Alali, U.; Vallin, A.; Bil, A.; Khanchouche, T.; Mathiron, D.; Przybylski, C.; Beaulieu, R. R.; Kovensky, J.; Benazza, M.; Bonnet, V.
Org. Biomol. Chem. 2019, 17, 7228-7237.
The homeostasis disruption of D-glucose causes diabetes, a dramatic world wide chronic disease. The type 1 diabetes is a succesfully treatable form, where the blood D-glucose is regulated by insulin treatement. In contrast the type 2 diabetes , the non Insulin dependent one, is problematic. The control of the D-glucose blood level via intestinal α-D-glucosidase inactivation can be achieved by using competitive inhibitors as iminosugars (e.g. acarbose) or sulfonium sugar derivatives (e.g. salacinol). Recently, an unprecedented result showed that multivalent diamond nanoparticules grafted with unmodified sugars displayed α-glucosidase inhibition at low micromolar concentrations. We describe herein the synthesis of multivalent glycoclusters using cyclodextrines (CDs) as scaffolds and their assessment as inhibithors of α-D-glucosidase. The glycoclusters were efficiently obtained from per-azido α, β and γ-CDs derivatives and propargyl glycosides using click-chemistry under microwave irradiation. The methodology was successfully applied to various protected and non-protected propargylated monosaccharides, including both O- and S- glycosides, giving clear evidences of its versatility. The targeted 6-per-glycosylated CDs were isolated in moderate to excellent yields (30-90 %) by silica gel chromatography. The results showed inhibition of α-glucosidase from Saccharomyces cerevisiae with IC50 values in a 32-132 µM range, lower than that of acarbose (IC50 ~250µM), a well knowm competitive inhibitor used in clinical treatment of type 2 diabetes. Preliminary experiments suggest a mixed-type non-competitive inhibition mode of these new glycoclusters.
https://dx.doi.org/10.1039/C9OB01344J

A microscale double labelling of GAG oligosaccharides compatible with enzymatic treatment and mass spectrometry
Przybylski, C.; Bonnet, V.; Vivès, R. R.
Chem. Commun. (Cambridge, U. K.) 2019, 55, 4182-4185.
A novel double labelling of glycosaminoglycans (GAG) oligosaccharides by thia-Michael addition and deuterium incorporation at the non-reducing and reducing ends, respectively, was introduced. This was demonstrated to be both compatible with the heparin microgram scale and amenable for mass spectrometry analysis, without impairing enzymatic activities such as heparinase I and sulfatase HSulf-2.
http://dx.doi.org/10.1039/C9CC00254E

Harnessing Polyisobutylene by Rotaxanation with γ-Cyclodextrin: Opportunities for Making Smart Molecular Necklaces
Przybylski, C.; Ramoul, H.; Bonnet, V.; Abad, M.; Jarroux, N.
Macromol. Chem. Phys. 0, 1800502.
Abstract A new type of polyrotaxane based on the threading of γ-cyclodextrins (γ-CDs) along a highly hydrophobic polymer, polyisobutylene (PIB), is successfully prepared and finely characterized. The used radical coupling associated with tuned reaction time and temperature leads to a fast and controlled necklace synthesis with low reagent consumption. Synthesis exhibits appealing conversion and threading rates with almost 100% and 62–73%, respectively. A combination of well-established SEC and NMR techniques, with a more forefront MALDI-TOF MS approach, provides details on the original PIB and the resulting polyrotaxanes (M w, M n, PDI, and average number of γ-CD threaded). Interestingly, tetramethylguanidinium-2-(4-hydroxyphenylazo)benzoate in DMF for MALDI analysis is revealed as a suitable matrix to overcome solubility troubles widely observed with PIB. Moreover, rotaxanation appears as an alternative to the grafting of polar groups to modify/handle hydrophobic polymers. Such an approach offers new opportunities to achieve the synthesis, with unambiguous evidence, of new supramolecular necklaces based on highly hydrophobic polymers.
http://dx.doi.org/10.1002/macp.201800502

Oleic Acid Based Cyclodextrins for the Development of New Hydrosoluble Amphiphilic Compounds
Cocq, A.; Rousseau, C.; Bricout, H.; Oliva, E.; Bonnet, V.; Djedaïni-Pilard, F.; Monflier, E.; Tilloy, S.
Eur. J. Org. Chem. 0.
A new family of amphiphilic cyclodextrins produced from oleic acid derivatives and maleic anhydride is described. These amphiphilic cyclodextrins are synthesized in two steps. The first step is the alkenylation of maleic anhydride by oleic acid derivatives to produce the oleic succinic anhydrides. The second step is the grafting of the oleic succinic anhydrides on various cyclodextrins. A self-inclusion of the alkyl chain or an inclusion of one alkyl chain in the cavity of another CD is showed by NMR experiments. The twelve amphiphilic cyclodextrins described possess high solubility in water (50–500 g/L at 20 °C) and low critical aggregation concentration (16–360 mg/L).
http://dx.doi.org/10.1002/ejoc.201801609

Nanoparticles based on lipidyl-β-cyclodextrins: synthesis, characterization, and experimental and computational biophysical studies for encapsulation of atazanavir
Furlan, A. L.; Buchoux, S.; Miao, Y.; Banchet, V.; Létévé, M.; Lambertyn, V.; Michel, J.; Sarazin, C.; Bonnet, V.
New J. Chem. 2018.
Amphiphilic cyclodextrins were synthesized from permethylated βCD with the aim of forming nanoparticles (NPs) that would encapsulate specific molecules (e.g. drugs) which could enhance their otherwise poor bioavailability. By grafting different fatty acids, four amphiphilic CDs were obtained. The self-assembling properties of three of these compounds were evaluated demonstrating micromolar critical aggregation concentration (CAC). Additionally, the stability of these nanoparticles was studied revealing that the compounds with C18 chains could be stored at 4 °C for prolonged periods without any issue. Finally, reliable characterization of NPs made of di-oleoyl-glycerolipidyl-β-cyclodextrin (DOCD) was performed by combining DLS, cryo-transmission electron microscopy (cryo-TEM) and molecular dynamics (MD) simulations. This revealed that DOCD nano-assemblies are roughly nano-scaled, spherical objects (diameter ca. 120 nm) without internal organization or aqueous compartments. Finally, atazanavir, used as a model drug, was entrapped in NPs whilst MD simulations were used to investigate molecule entrapment. This revealed that atazanavir interacts with DOCD to form a drug-loaded NP which does not fit with the 2 : 1 stoichiometry encapsulation classically observed in the cyclodextrin cav
http://dx.doi.org/10.1039/C8NJ03237H

Revealing cooperative binding of polycationic cyclodextrins with DNA oligomers by capillary electrophoresis coupled to mass spectrometry
Przybylski, C.; Benito, J. M.; Bonnet, V.; Mellet, C. O.; García Fernández, J. M.
Anal. Chim. Acta 2018, 1002, 70-81.
Gene delivery is critical for the development of nucleic acid-based therapies against a range of severe diseases. The conception of non-viral (semi)synthetic vectors with low cytotoxicity and virus-like efficiency is gathering a lot of efforts, but it represents a fantastic challenge still far from accomplishment. Carbohydrate-based scaffolds offer interesting features towards this end, such as easy availability, relatively cheap cost, tuning properties and a good biocompatibility. The lack of analytical methods providing quantitative and qualitative data on their binding properties with oligonucleotides (DNA/RNA), with a minimal time and sample consumption, represents a limitation for these channels. Here, we attempted to fill the gap by hyphenation of capillary electrophoresis with mass spectrometry (CE-MS). This coupling strategy allows discriminating free and complexed DNA oligomers with cationic cyclodextrins (CDs), determining the stoichiometry where the highest observed is always DNAn: n/3(CD), and unambiguously assigning the partners through m/z detection. Very reliable data were obtained with migration time within 5.5 (standard deviation < 0.5%) and 25 min (standard deviation < 1.1%) for UV and MS detection, respectively. Furthermore, varying the nitrogen/phosphorus ratio (N/P), key parameters relating to the thermodynamics e.g. the micro and macroscopic dissociation constants Kd and KD, respectively (both in low μM range) and the Gibbs free energy ΔG (−16.3 to −26.9 kJ mol−1), and also the cooperativity as Hill number (nH between 0.98 and 15.75) of the supramolecular process can be delineated, providing a unique tool for the high throughput screening and selection of efficient gene delivery carriers.
http://dx.doi.org/10.1016/j.aca.2017.11.034

Physico-chemical studies of resveratrol, methyl-jasmonate and cyclodextrin interactions: an approach to resveratrol bioproduction optimization
Oliva, E.; Mathiron, D.; Bertaut, E.; Landy, D.; Cailleu, D.; Pilard, S.; Clément, C.; Courot, E.; Bonnet, V.; Djedaïni-Pilard, F.
RSC Advances 2018, 8, 1528-1538.
trans-Resveratrol (RSV) is a natural phenolic molecule of the stilbene family known for its anti-oxidant properties in the field of nutraceuticals and cosmetics. Its production by grapevine cell suspensions is induced by the addition to the culture medium of elicitor compounds, methyl jasmonate (MeJA) and cyclodextrins (CDs). Physico-chemical studies were performed to understand the mechanism of action of CDs on this bioproduction of RSV. Inclusion complexes of RSV in CDs were first observed and then interactions with MeJA were identified using various analytical techniques such as UV and nuclear magnetic resonance (NMR) spectroscopies, mass spectrometry (MS) and isothermal titration calorimetry (ITC).
http://dx.doi.org/10.1039/c7ra11619e

La chimie en Région Hauts-de-France : Chimie, biologie et santé
Stéphane Lebrun, V. A., Philippe Amouyel, Christophe Biot, Véronique Bonnet, Benoit Deprez, Pierre André Gilormini, Cédric Lion, Oleg Melnyk, Patricia Melnyk et Jérôme Vicogne
Actualité Chimique 2017, 46-51.
Cet article présente un tour d’horizon de quelques-unes des thématiques de recherche développées en région Hauts-de-France dans les domaines de la chimie, de la biologie et de la santé.
http://www.lactualitechimique.org/Chimie-biologie-et-sante

Deciphering of polycationic carbohydrate based non-viral gene delivery agents by ESI-LTQ-Orbitrap using CID/HCD pairwise tandem mass spectrometry
Przybylski, C.; Benito, J. M.; Bonnet, V.; Mellet, C. O.; Garcia Fernandez, J. M.
RSC Advances 2016, 6, 78803-78817.
For almost three decades, gene therapy has been gaining interest to efficiently treat some severe diseases. In such context, the discovery of an efficient non-viral gene carrier to deliver genetic material into targeted cell nuclei is of prime importance. Numerous synthetic vectors that have been designed exhibit high transfection efficiency but also suffer from extensive cytotoxicity, thus justifying efforts to synthesize more bio-compatible ones, for example, with carbohydrate scaffolds. In this sense, cyclodextrins (CDs) are well known to present low to very low cytotoxicity in humans and have potential, after polycationization, to serve as suitable compaction/transfection agents for RNA/DNA. However, such polycationic CDs must be accurately characterized to establish a straightforward structure-biological activity relationship which is guided by the nitrogen/phosphorus ratio (N/P). In the study herein, we demonstrated that electrospray-(tandem) mass spectrometry (ESI-(MS)MS) combining Collision Induced Dissociation (CID) and Higher Collision induced Dissociation (HCD) is a useful tool for such synthetic agent characterization. The suitability of CID/HCD pairwise combination was investigated for the structural deciphering of five representative members of a polycationic cyclodextrin library. Our approach allows for easy access to content, type and localisation of amino groups thereby offering a useful tool to correlate the synthetic delivery agent with effective compaction of oligo-/polynucleotides.
http://dx.doi.org/10.1039/C6RA14508F

Radical Coupling Allows a Fast and Tuned Synthesis of Densely Packed Polyrotaxanes Involving γ-Cyclodextrins and Polydimethylsiloxane
Blin, F.; Przybylski, C.; Bonnet, V.; Clément, M.-J.; Curmi, P. A.; Choppinet, P.; Nakajima, T.; Chéradame, H.; Jarroux, N.
Macromolecules 2016, 49, 3232-3243.
The first radical end-coupling synthesis of polydimethylsiloxane (PDMS)−γ-cyclodextrins (γ-CDs) based polyrotaxane is reported. Conversely to usual chemical way, the radical process leads to fast both controlled size and structure with minimal side reaction while exhibiting very high conversion rate (w/w, 80%). Pure PDMS−γ-CDs molecular necklaces were successfully isolated by preparative size exclusion chromatography and finely characterized both by 1D/2D/STD 1H and 13C NMR and MALDI-TOF mass spectrometry. The observations give clear evidence of the supramolecular assembly synthesis where the filling ratio (γ-CD/monomer unit) of PDMS chains is as high as 40% of γ-CDs. Combination of such radical-based coupling supported by detailed analytical characterizations appears at the forefront of a fast, suitable, and easily amenable scaling-up CDs-based polyrotaxane synthesis process.
http://dx.doi.org/10.1021/acs.macromol.6b00492

Probing the common alkali metal affinity of native and variously methylated [small beta]-cyclodextrins by combining electrospray-tandem mass spectrometry and molecular modeling
Przybylski, C.; Bonnet, V.; Cezard, C.
Phys. Chem. Chem. Phys. 2015, 17, 19288-19305.
In the study herein, we investigated the solution and gas phase affinity of native and variously methylated [small beta]-cyclodextrins (CDs) as hosts towards three common alkali metals as guests namely lithium, sodium and potassium. For this purpose, two complementary approaches have been employed: electrospray-tandem mass spectrometry (ESI-MS/MS) with two energetic regimes: Collision Induced Dissociation (CID) and Higher Collision Dissociation (HCD), respectively, and DFT molecular modeling. These approaches have been achieved by taking into account the interaction of either one or two alkali metals with the host molecules. The results showed a good agreement between experimental and theoretical data. It was demonstrated that increasing the methylation degree strengthened the gas phase affinity towards all studied alkali metals. Furthermore, it was established that the cation selectivity was Na+ > Li+ > K+ and Li+ > Na+ > K+ for the solution and gas phase, respectively.
http://dx.doi.org/10.1039/C5CP02895G

Cyclodextrin nanoassemblies: a promising tool for drug delivery
Bonnet, V.; Gervaise, C.; Djedaïni-Pilard, F.; Furlan, A.; Sarazin, C.
Drug Discovery Today 2015, 20, 1120-1126.
Among the biodegradable and nontoxic compounds that can form nanoparticles for drug delivery, amphiphilic cyclodextrins are very promising. Apart from ionic cyclodextrins, which have been extensively studied and reviewed because of their application in gene delivery, our purpose is to provide a clear description of the supramolecular assemblies of nonionic amphiphilic cyclodextrins, which can form nanoassemblies for controlled drug release. Moreover, we focus on the relationship between their structure and physicochemical characteristics, which is crucial for self assembly and drug delivery. We also highlight the importance of the nanoparticle technology preparation for the stability and application of this nanodevice.
http://dx.doi.org/10.1016/j.drudis.2015.05.008

Cyclodextrin-grafted polymers functionalized with phosphanes: a new tool for aqueous organometallic catalysis
Potier, J.; Menuel, S.; Mathiron, D.; Bonnet, V.; Hapiot, F.; Monflier, E.
Beilstein J. Org. Chem. 2014, 10, 2642-2648, 7 pp.
New cyclodextrin (CD)-grafted polymers functionalized with water-sol. phosphanes were synthesized in three steps starting from N-succinimidyl acrylate homopolymer. Once characterized by NMR spectroscopy and size-exclusion chromatog., they were used as additives in Rh-catalyzed hydroformylation of 1-hexadecene. The combined supramol. and coordinating properties of these polymers allowed increasing the catalytic activity of the reaction without affecting the selectivities.
http://dx.doi.org/10.3762/bjoc.10.276

A green approach to the synthesis of novel phytosphingolipidyl β-cyclodextrin designed to interact with membranes
Miao, Y.; Djedaini-Pilard, F.; Bonnet, V.
Beilstein J. Org. Chem. 2014, 10, 2654-2657, 4 pp.
This work reports the synthesis of a new family of mono-substituted amphiphilic cyclodextrins using a green methodol. Reactions using greener and safer catalysts with more environmentally friendly purifn. solvents were performed. Four unreported mono-substituted cyclodextrins bearing a phytosphingolipidyl chain and a fatty acid chain (C10, C12, C14 and C18) were successfully obtained with a promising yield.
http://dx.doi.org/10.3762/bjoc.10.278

Diesterification of 3-[(β-Cyclodextrinyl)succinamido]propane-1,2-diol Catalysed by Lipase: Diastereoselectivity or Tridimensional Substrate Specificity?
Gervaise, C.; Bonnet, V.; Nolay, F.; Cezard, C.; Stasik, I.; Sarazin, C.; Djedaini-Pilard, F.
Eur. J. Org. Chem. 2014, 2014, 6200-6209.
The transesterification of 3-[(β-cyclodextrinyl)succinamido]propane-1,2-diol with fatty esters catalyzed by immobilized lipase from Mucor miehei occurred with very different conversions of the two diastereoisomers [(R)- or (S)-amidopropanediol]. The highest conversion obsd. with the (S)-amidopropanediol can be related to either lipase diastereoselectivity or substrate specificity. To investigate the diastereoselectivity of the lipase, diastereoisomers of the methylated β-cyclodextrin were replaced by methylated glucopyranoside or methylleucine. No discrimination of the diastereoisomers by lipase was obsd. Mol. modeling was performed to assess the lipase selectivity towards the two diastereoisomers. It was found that the (R)-amidopropanediol is stabilized by hydrogen bonding with the cyclodextrin rim resulting in less reactive hydroxy groups.
http://dx.doi.org/10.1002/ejoc.201402414