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International audience; The synthesis of two new fluorescent hemicryptophanes is reported. They were found to be efficient and selective receptors for acetylcholine over choline. When compared to other hemicryptophane hosts previously reported for the selective recognition of acetylcholine, they display improved fluorescent properties: their maximum emission wavelengths are red-shifted and the quantum yields are higher. NMR titration experiments and density functional theory (DFT) calculations support the results obtained from fluorescence spectroscopy and give insights into the interactions involved in the host/guest complexes and into the selectivity for acetylcholine over choline.

International audience; A new off-on fluorescent hemicryptophane probe for acetylcholine has been designed. This hemicryptophane, made fluorescent via an extension of the conjugation of its cyclotriveratrylene C3-symmetry part, exhibits improved fluorescence properties compared with fluorescent hemicryptophanes previously described. Indeed, both the excitation and emission wavelengths are red-shifted and the quantum yield is increased. Moreover, this hemicryptophane is able to bind acetylcholine with a high association constant of 3.2 × 104 M-1. This recognition process is accompanied by an increase in the brightness of the capsule. Surprisingly, contrary to what is commonly observed with cyclotriveratrylene-based hosts, the quaternary ammonium of the guest interacts with the tris(2-aminoethyl)amine south part of the hemicryptophane instead of the cyclotriveratrylene north part. This unusual binding mode is supported by both proton NMR experiments and density functional theory calculations.

To study the effect of the structure of 3,3′-modified bipyridyl ruthenium complexes on their ability to recognize organic anions, various ruthenium complexes have been prepared. The binding functions and large-sized modified bipyridyl ligand turned out to be essential for selectivity in acetonitrile. The selectivity for dicarboxylates or phosphates can be switched by using guanidinium- or ammonium-functionalized probes. One of these probes turned out to be selective towards glutamate over aspartate and γ-aminobutyric acid (GABA). Another was selective towards adenosine 5′-triphosphate (ATP) over adenosine 5′-diphosphate (ADP), pyrophosphate (PPi), adenosine 5′-monophosphate (AMP), and orthophosphate (Pi). In both cases, the binding was attributed to coulombic interactions and hydrogen bonding. π-stacking interactions also occurred with nucleotides. Replacing ammonium by zinc-dipicolylamine units made possible the recognition of phosphorylated species in buffered aqueous systems. To our delight, this probe showed selectivity for ADP over ATP and we proved that the selectivity was partly due to substitution at the 3- and 3′-positions of the ligand.

International audience; A fluorescent hemicryptophane has been synthesized and can beused as a turn on receptor of acetylcholine. A binding constant of2.4 × 104M−1was measured for this neurotransmitter, and itsselective and sensitive detection over choline and choline phos-phate was achieved. NMR and DFT calculations provide insight intothe interactions involved in this selective recognition process

New gallium(III) and iron(III) endohedral complexes were obtained from a hemicryptophane ligand bearing suitable binding sites for octahedral metal coordination. The solid-state structures of the free host and of the complexes were determined by single-crystal X-ray diffraction analysis. The metal ion is linked to the hydrazone nitrogen and the phenolate oxygen atoms, yielding a distorted octahedral geometry around the encapsulated metal. The two isomorphous structures of the metal complexes reveal the exclusive formation of PΔ/MΛ enantiomeric pairs.

We report here the electrochemical characterization of eight synthetic DNA intercalators based on the 4H-pyrido[4,3,2- kl ]acridin-4-one structure. We found that the electrochemical behavior of these redox active drugs is strongly influenced by the nature of the solvent. A single two-electron reduction is observed in an aqueous phosphate buffer (PB) whereas two successive one-electron reductions are observed in aprotic solution (acetonitrile). The influence of the molecular structure on the potential values is addressed along with a comparison between the DNA binding constant ( K DNA ) and the cytotoxic activity against HT29 cells (IC 50 ). For typical DNA intercalators, one could expect that toxicity will be roughly proportional to the DNA binding constant. Yet, a structure/activity comparison solely based on the DNA affinity was not conclusive. In contrast, a direct relationship was evidenced for the first time between the decimal logarithm of the in vitro bioactivity and the reduction potential of pyridoacridones recorded in PB at pH 7.0. Moreover, most of the bio/electrochemical relationships previously described for quinone-based drugs were reported with electrochemical characterization in aprotic solvents (typically acetonitrile, dimethylformamide or dimethylsulfoxide). But aqueous solution electrochemistry is definitely the most bio-relevant because the redox mechanism of quinone or iminoquinone reduction directly depends on the protic nature of the solvent.

International audience; Cyclotriveratrylene analogues (CTVs) are supramolecular bowl-shaped molecules known for their ability to complex organic and organometallic guests, to form liquid crystals, polymers, or nanostructures. In this Article, we report the synthesis of new cyclotriveratrylene analogues with fluorescence properties in which various electron-withdrawing or π-extended conjugated groups are appended to the wide rim ortho to the methoxy-donating groups. Synthetically, these functionalized CTVs cannot be obtained as CTVs with electron-rich functions by the typical method (i.e., the trimerization of the corresponding benzyl alcohol) but are prepared from a common key intermediate, the C3-triiodocyclotriveratrylene (CTV-I3), in good yields. Despite the synthetic difficulties encountered due to the presence of three reactive centers, we have demonstrated the possibility of performing Sonogashira coupling and Huisgen cycloaddition reactions directly to the CTV core for the first time. CTVs with π-extended conjugated groups reveal interesting fluorescence profiles. More broadly, this study utilizes CTV-I3 to introduce novel functionalities into CTVs to keep exploring their potential applications. Cyclotriveratrylene analogues (CTVs) are supramolecular bowl-shaped molecules known for their ability to complex organic and organometallic guests, to form liquid crystals, polymers, or nanostructures. In this Article, we report the synthesis of new cyclotriveratrylene analogues with fluorescence properties in which various electron-withdrawing or π-extended conjugated groups are appended to the wide rim ortho to the methoxy-donating groups. Synthetically, these functionalized CTVs cannot be obtained as CTVs with electron-rich functions by the typical method (i.e., the trimerization of the corresponding benzyl alcohol) but are prepared from a common key intermediate, the C3-triiodocyclotriveratrylene (CTV-I3), in good yields. Despite the synthetic difficulties encountered due to the presence of three reactive centers, we have demonstrated the possibility of performing Sonogashira coupling and Huisgen cycloaddition reactions directly to the CTV core for the first time. CTVs with π-extended conjugated groups reveal interesting fluorescence profiles. More broadly, this study utilizes CTV-I3 to introduce novel functionalities into CTVs to keep exploring their potential applications.

Little is known about the ability of α-linolenic acid (Ln) to remain in the sn-2 position of TG during the absorption process. The goal of this study was to determine the Ln distribution in the lymph (Study 1) and plasma (Study 2) TG of rats fed a single i.g. load of structured TG [300 mg/rat of either oleic acid (O)/Ln/O TG (OLnO) or Ln/O/O TG (LnOO), n = 7 rats]. In an early fraction (3-4 h) of lymph (OLnO group; 100% Ln in the sn-2 position), 46 ± 2% Ln was maintained in this position in lymph TG. There was even less (29 ± 6%) in the last fraction (7-24 h) (P < 0.05). Ln was also found (9 ± 3%) in the sn-2 position of lymph TG in the LnOO group. The Ln content in lymph phospholipids was twice as high in rats when they were fed LnOO (4.2 ± 0.1%) than OLnO (2.3 ± 0.2%) (P < 0.005). Six hours postprandially (Study 2), 21 ± 3% of the Ln incorporated into plasma TG was located in the sn-2 position in the OLnO group compared to 13 ± 2% in the LnOO group (P < 0.001). Overall, these results indicate that the amount of Ln that moved from the sn-2 position of structured TG to the sn-1(3) position of lymph TG increased during absorption. This may account for a substantial hydrolysis of the 2-monolinolenylglycerols in enterocytes, leading to the intramolecular redistribution of Ln in lymph TG and, consequently, in plasma TG.

We report on the synthesis of various glucose-responsive microgels based on N-alkylacrylamide derivatives and phenylboronic acid (PBA) as a glucose sensing moiety. Depending on their chemical composition, the microgels exhibit opposite behaviors in response to glucose concentration increase: they can either swell or shrink, using two different mechanisms for glucose recognition. Both behaviors may be suitable for glucose sensing and insulin delivery. When glucose binds a single boronate receptor, the microgel swells as glucose concentration increases. This mechanism can be used to deliver a drug by diffusion through the network. In other cases, glucose binds specifically to two boronates, which creates additional cross-links within the network and provokes shrinkage. Such systems are promising for the development of sensors with improved selectivity and also as potential "intelligent" valves in microfabricated delivery systems. By a rational choice of the constituting units of the network structure, we show how to favor one or the other type of response to glucose variation. Therefore, glucose-swelling microgels operating under physiological conditions have been obtained by copolymerization with an appropriate choice of alkylacrylamide monomer and boronate derivative. At a pH above the pK(a) of the boronic acid derivative, the same structures shrink in response to glucose concentration. The nature of the cross-linker is a key parameter to enable this dual behavior. In other microgels, an amine group is introduced in the vicinity of the boronic acid, which lowers its pK(a) and favors microgel contraction at physiological pH. This work has allowed us to give some general rules to control the swelling/shrinking behavior of glucose-responsive microgels.

Stimuli-responsive microgels with redox and luminescent resonance energy transfer (LRET) properties are reported. Poly(N-isopropylacrylamide) microgels are functionalized simultaneously with two models dyes: a derivative of tris(bipyridine) ruthenium complex and cyanine 5. Both moieties are chosen as a pair of luminophores with a spectral overlap for resonance energy transfer, where the ruthenium complex acts as a donor and the cyanine an acceptor. The effect of the temperature on the efficiency of the LRET of the microgels has been investigated and compared using either photoluminescence (PL) or electrochemiluminescence (ECL) as the excitation process. In PL, the synthesized microgels exhibit resonance energy transfer regardless of the swelling degree of the microgels. The transfer efficiency is a function of the donor-acceptor distance and can be tuned either by the swell-collapse phase transition or by the dye content in the microgel network. In ECL, the microgels emit light only at the wavelength of the ruthenium complex because the resonance energy transfer does not occur. Indeed, even within the microgel matrix, the cyanine dye is oxidized at the potential required for ECL generation, which impairs its emitting properties. Thus, both excitation channels (i.e., PL and ECL) show differential behavior for the resonance energy transfer processes.

We report synthesis, characterisation and molecular modelling of a new fluorescent cyclotriveratrylene probe for acetylcholine in aqueous media, with emission around 430 nm thanks to extended conjugation. The probe discriminates acetylcholine from choline, with respective binding constants 540 and 240 M(-1) in PBS buffered saline solution, an order of magnitude improvement over the previous best performance. Dynamic light scattering and transmission electron microscopy show the new probe self-assembles in ca. 5 nm diameter particles in PBS medium. Molecular modelling suggests that the high fluorescence quantum yield of the probe, 20% in aqueous media, is due to features of the molecular arrangement in the nano-particles, contributing both to exposure of the complexation site and to shielding of the fluorescent π system from quenching by water. Titration data for other quaternary ammoniums and modelling indicate that recognition of acetylcholine vs. choline depends on specific electrostatic interactions, and to a lesser extent on exclusion of water by hydrophobic-hydrophilic segregation. Probe-substrate interactions enhance the fluorescence of the probe by shielding against water and by flattening the π system.

The preparation of new 25,27-bis(alkyloxy)calix[4]arenes-crown-6 in the cone, partial-cone and 1,3-alternate conformation is reported. We have also investigated the alkylation of the cone monoalkylated calix[4]arene-crown-6 achieved using Cs 2 CO 3 . This reaction afforded a mixture of cone and partial-cone calix[4]arenes-crown-6 having an alkyl chain anti or syn to the polyether ring. Conformations have been probed using 1 H, 13 C, 2D-NMR and NOESY analysis, and using X-ray crystallography. Extraction experiments using a two-phase solvent method involving cesium picrate were performed for these newly synthesized conformers. They reveal and confirm the strong preference for the 1,3-alternate conformers. The affinity of 1,3-alternate calixarenes for Cs + has been assessed by complexation measurements (log g ) using a spectrophotometric technique. No significant Cs + extraction difference was observed in relation to the nature of the alkyl chains on the aromatic rings. 1 H NMR studies of the 1,3-alternate c...

International audience; An efficacious strategy to obtain photostable Hyper-bright near-IR emitting Fluorescent Organic Nanoparticles (HIFONS) is reported. These HIFONs show excellent chemical and colloidal stability and retain their pristine nanostructure and brightness after incubation in cellular environments. They can be identified at the single particles level with a wide-field microscope, emerging as highly promising tools for applications in bionanotechnologies.

The reaction of the tri-(benzaldehyde)-substituted cyclotriveratrylene 6 with phosphotrihydrazide under high dilution conditions gives rise to the novel thiophosphorylated hemicryptophane 1. 1 is representative of a new family of molecular receptors providing a molecular cavity available for neutral and charged guests. In the crystal, compound 1 encapsulates one toluene molecule. Un he′micryptophane thiophosphoryle′: structure du complexe d'inclusion avec le toluene. La re′action du cyclotrive′ratrylene 6, trisubstitue′ par des groupements benzalde′hyde, avec le phosphotrihydrazide dans des conditions de haute dilution, conduit au nouveau he′micryptophane 1. 1 repre′sente une nouvelle famille de re′cepteurs mole′culaires contenant une cavite′ pouvant pie′ger des substrats neutres ou charge′s. Dans le cristal, le compose′ 1 encapsule une mole′cule de toluene.

New supramolecular phosphorus receptors with conformationally rigid structures were investigated. Tetraphosphonate-calix[4]resorcinarenes with long chain substituents on the resorcinolarene unit were synthesized in fairly good yields. The all in (iiii) stereoisomer was preferentially obtained. The phosphacavitands exhibit an extremely large affinity for metallic and ammonium cations, which is due to the complementary positioning of a “soft” lipophilic cavity and “hard” phosphorylated binding sites, leading to cooperative binding interactions. The formation of a thio-phosphorylated hemicryptophane, bearing a phosphotrihydrazone moiety, is also reported. It forms stable complexes with neutral aromatic guests and provides a novel synthetic approach to the design of new metallo-receptors.

International audience; A new strategy to obtain fluorescent cyclotriveratrylene (CTV) probes is proposed. The key intermediate, a triiodo CTV, is prepared in 3 steps with 47% overall yield. The whole synthesis requires only one purification step. The potential of this triiodo CTV as an intermediate is illustrated through the synthesis of a fluorescent phosphorylated probe that is able to bind choline and acetylcholine in pseudo-physiological conditions, with selectivity towards choline. As a consequence, this intermediate should allow us to rapidly form a library of probes in order to highlight the most promising ones.

Little is known about the ability of α-linolenic acid (Ln) to remain in the sn-2 position of TG during the absorption process. The goal of this study was to determine the Ln distribution in the lymph (Study 1) and plasma (Study 2) TG of rats fed a single i.g. load of structured TG [300 mg/rat of either oleic acid (O)/Ln/O TG (OLnO) or Ln/O/O TG (LnOO), n = 7 rats]. In an early fraction (3-4 h) of lymph (OLnO group; 100% Ln in the sn-2 position), 46 ± 2% Ln was maintained in this position in lymph TG. There was even less (29 ± 6%) in the last fraction (7-24 h) (P0.05). Ln was also found (9 ± 3%) in the sn-2 position of lymph TG in the LnOO group. The Ln content in lymph phospholipids was twice as high in rats when they were fed LnOO (4.2 ± 0.1%) than OLnO (2.3 ± 0.2%) (P0.005). Six hours postprandially (Study 2), 21 ± 3% of the Ln incorporated into plasma TG was located in the sn-2 position in the OLnO group compared to 13 ± 2% in the LnOO group (P0.001). Overall, these results indicate that the amount of Ln that moved from the sn-2 position of structured TG to the sn-1(3) position of lymph TG increased during absorption. This may account for a substantial hydrolysis of the 2-monolinolenylglycerols in enterocytes, leading to the intramolecular redistribution of Ln in lymph TG and, consequently, in plasma TG.

Different lights, different selectivies: Luminescence of a new guanidinium 3,3′-functionalized bipyridyl–RuII complex has been studied for sensing of several anions. L-Glutamate and dihydrogenphosphate are both detected by photoluminescence and electrochemiluminescence. However, the complex displays differential selectivities for these anions depending on the sensing channels (see scheme). A new guanidinium 3,3′-functionalized bipyridylruthenium(II) complex has been prepared for the differential sensing of L-glutamate and dihydrogenphosphate anions depending on the luminescent detection scheme. The effects of such anions on the photoluminescent (PL) and electrochemiluminescent (ECL) properties of the complex have been investigated and compared. The PL intensity increases up to fourfold in the presence of L-glutamate. The increase of intensity in the presence of dihydrogenphosphate is weaker and no change in PL intensity is observed in presence of acetate, iodide, or chloride anions. With n-tripropylamine, ECL emission of the RuII complex is initiated at 1.45 V versus Ag/AgCl/KCl and the ECL intensity increases only in the presence of dihydrogenphosphate. Indeed, L-glutamate is already oxidized at the relatively high potential required for ECL generation and thus it does not affect the ECL signal. The comparison of the competitive ECL and PL assays in a mixture of anions confirms the differential detection of L-glutamate and of dihydrogenphosphate. Thus, both sensing channels (i.e., PL and ECL) show different selectivities depending on the nature and on the electroactivity of the target anions. Multianion analysis is demonstrated in competitive assays using complementary detection methods.

Monodispersed poly(N-isopropylacrylamide) submicrometric microgels modified with a phenylboronic acid (PBA) derivative have been synthesized by precipitation polymerization. Particles with a well-controlled size and adjustable composition were obtained. These particles were found to be glucose responsive at a pH close to the pKa of the PBA derivative, with a swelling degree proportional to the concentration of glucose. In addition, the response to glucose was found to strongly depend on the initial state of the microgel, which depended itself on the initial temperature and the functionalization degree of the particle. This result explained the fundamental difference in the behavior of PBA-poor particles and rich ones in the presence of electrolyte. Interestingly, the latter exhibited a high swelling ratio in the presence of glucose at physiological electrolyte concentration. These particles may serve as building blocks for the design of colorimetric sensors based on the light diffraction of colloidal crystals.

The new amphiphatic cryptophanes M5 and M6 were synthesized from their precursor M4. They present interesting properties due to their long chain substituents on one of the cyclotriveratrylene moieties. M4 was synthesized from a thio-cyclotriveratrylene platform obtained from thio-vanillin, using the template method developed for the preparation of dissymmetrical cryptophanes. The tris-hexanol (M5) or tris-hexadecyl (M6) substituted cryptophanes exhibited enhanced amphiphatic properties, which were investigated through the π–A isotherms of the interfacial films obtained at the air–water interface (Langmuir monolayers). The corresponding surface elasticity coefficients of the films were determined and their stability analyzed at different surface pressures. Stable molecular films of M5 were obtained after a first compression step, suggesting a rearrangement of the molecules at the interface. This behavior matched with a reduction of the molecular area consistent with the formation of bilayers of M5 molecules. Cryptophane M6 formed stable and reversible Langmuir monolayers at higher surface pressure (πmax = 27 mN m−1). This was attributed to interactions between the long alkyl chain substituents of the cryptophane, which favor the organization of the molecules on the water subphase. At higher pressure both compounds form aggregates irreversibly.

International audience; New amide-containing ferrocenyl ligands, L1–5, were prepared and the voltammetric and 1H NMR investigations of anion binding were carried out in organic media. The electrochemical recognition ability of L1–5 towards F−, HSO4−, H2PO4− and ATP2− is based on the synergy between H-bonding to amide protons in anion complexation to reduced, neutral ligands and ion-pairing interactions developed with the oxidized, cationic form of the ligands. The strength of the anion–ligand interactions depends on the number of ferrocene centers and amide groups in the receptor, and on the accessibility of the binding sites. Clear two-wave cyclic voltammetry features allowed the amperometric titration of H2PO4− and ATP2− by ligands L4 and L5 built from a cyclotriveratrylene structural unit, and containing a combination of three ferrocene centers with three (L4) or six (L5) amide groups.

A photochromic dithienylethene, bearing a phenyl azacrown as an ionophore and a formyl group as an electron-accepting substituent, changes its binding ability for Ca2+ by a factor higher than 103 by photoirradiation. This new photoionochromic displays a wavelength-dependent competition between fluorescence and photocyclization assigned to a red-shifted absorption of the fluorescing conformer compared to the absorption of the photoreactive conformer.

Neurodegenerative diseases like Alzheimer, Parkinson or Huntington are related to an imbalance of neurotransmitters. Nevertheless, the sources of this neuronal communication disorder are not well-understood to date, partly because of the lack of tools allowing real-time and real-space monitoring of neurotransmitters, in biological systems. Thus, it is extremely important to develop tools such as fluorescent supramolecular probes for the imaging of neurotransmitters.In a previous study carried out in our groups, fluorescent probes based on a cyclotriveratrylene skeleton, able to recognize either choline or acetylcholine (ACh) in buffer aqueous solution (pH 7.4), have been synthesized. However, these molecules do not respect all the criteria needed for the imaging of species in biological conditions. Indeed, their complexation constants are insufficient. To improve the binding affinity between probes and neurotransmitters we turned our attention to capsules built from cyclotriveratrylene core, namely hemicryptophanes (HC). HC are known to bind ammoniums guests thanks to their preorganized cavity. New fluorescent hemicryptophanes were synthesized. The synthetic pathway we developed allow us to easily modify the HC’s fluorescent moiety. Some of them show good affinities for different neurotransmitters like acetylcholine, dopamine, serotonin, good sensitivities and are soluble in buffer aqueous solution. Their synthesis as well as their fluorescence and recognition properties will be presented., Les maladies neurodégénératives comme la maladie d'Alzheimer, la maladie de Parkinson ou celle d'Huntington sont liées à un déséquilibre des neurotransmetteurs. Néanmoins, les sources de ces troubles de communication neuronale ne sont pas bien compris à ce jour, en partie à cause du manque d'outils permettant de suivre en temps réel et dans l'espace les neurotransmetteurs, dans les systèmes biologiques. Ainsi, il est extrêmement important de développer des outils tels que des sondes supramoléculaires fluorescentes pour l'imagerie des neurotransmetteurs.Dans une étude précédente réalisée dans notre groupe, des sondes fluorescentes basées sur un squelette cyclotriveratrylene, capables de reconnaître la choline ou l'acétylcholine (ACh) en solution aqueuse tampon (pH 7.4), ont été synthétisées. Cependant, ces molécules ne respectent pas tous les critères nécessaires à l'imagerie des espèces dans des conditions biologiques. En effet, leurs constantes de complexation sont insuffisantes. Pour améliorer l'affinité de liaison entre les sondes et les neurotransmetteurs, nous avons tourné notre attention vers des capsules construites à partir du noyau de cyclotriveratrylene, à savoir les hémicryptophanes (HC). Les hémicryptophanes sont connus pour reconnaître les invités ammoniums grâce à leur cavité préorganisée. De nouveaux hemicryptophanes fluorescents ont été synthétisés. La voie synthétique que nous avons développée nous permet de modifier facilement le motif fluorescent de l'HC. Certains d'entre eux montrent de bonnes affinités pour différents neurotransmetteurs comme l'acétylcholine, dopamine, sérotonine, ainsi qu'une bonne sensibilité et sont solubles dans la solution aqueuse tampon. Leur synthèse ainsi que leurs propriétés de fluorescence et de reconnaissance seront présentées.