Cobalt tris(4-vinylphenyl)corrole: out of the frying pan into the polymer.

A novel cobalt corrole bearing 4-vinylphenyl groups at the 5,10,15-meso-positions of the macrocycle has been synthesized from tris(4-bromophenyl)corrole using a Suzuki coupling reaction. The spectral and electrochemical properties are reported in CH2Cl2 along with its ability to form a highly stable six-coordinate complex and cross-linked corrole-based polymer in a 59% yield.

[The Double degree in Health and Sciences Curriculum at the Rouen Health UFR: Current situation and perspectives]. / Le Double Cursus Santé Sciences à l'UFR Santé de Rouen - États des lieux et perspectives.

The Double degree in Health and Sciences (DCSS) provides an early training in research for future healthcare professionals. The profound transformation of the healthcare system and the advent of new analytical and digital technologies highlight the urgent need to link research to clinical practice. At the international level, especially in the United States, these programs point out the key role of healthcare professionals with both medical and scientific expertise. In France, a DCSS during medical studies was set up in the 2000's. This training is still heterogeneous and is not organized in all Faculties of Health Sciences. The Rouen Faculty of Health Sciences observed in 2016 that the number of students involved in DCSS was very low or even zero, depending on the year. The Rouen Faculty of Health Sciences initiated an institutional support in 2017 that led to the creation of a student mentorship dedicated to DCSS. This mentorship and the institutional leaders of this course have initiated a theoretical and practical training program. The organization of the DCSS of the Rouen Faculty of Health Sciences and the creation of a student mentorship program enabled us to increase the number of candidates interested in the DCSS (from 2 in 2016 to 26 in 2021) and to obtain an institutional recognition of this double major.

Title: Le Double Cursus Santé Sciences à l'UFR Santé de Rouen - États des lieux et perspectives. Abstract: Le Double Cursus Santé Sciences (DCSS) permet de former précocement les futurs acteurs de santé à la recherche. La profonde transformation du système de santé et l'avènement de nouvelles techniques analytiques et numériques ont conduit à reconsidérer la place de la recherche dans la pratique clinique. L'expérience internationale de ce type de programme de formation, notamment aux États-Unis, a révélé le rôle prépondérant que jouent les acteurs de santé ayant acquis une double compétence, médicale et scientifique. En France, un DCSS précoce, pendant les études médicales, a été mis en place dans les années 2000. Cette formation reste cependant disparate et hétérogène, et ne concerne pas toutes les universités. En 2016, l'UFR Santé de Rouen a constaté que le nombre d'étudiants engagés dans ce double cursus était très faible, voire nul selon les années. Aussi, en 2017, un accompagnement institutionnel a été introduit. Celui-ci a abouti à la création d'un tutorat étudiant dédié à cette formation. Il a permis une augmentation du nombre de candidats intéressés et la reconnaissance institutionnelle de ce double parcours. Nous présentons ici les contours de cette formation impliquant étudiants et institution.

Cyclodextrins: promising scaffolds for MRI contrast agents.

Magnetic resonance imaging (MRI) is a powerful tool for non-invasive, high-resolution three-dimensional medical imaging of anatomical structures such as organs and tissues. The use of contrast agents based on gadolinium chelates started in 1988 to improve the quality of the image, since researchers and industry focused their attention on the development of more efficient and stable structures. This review is about the state of the art of MRI contrast agents based on cyclodextrin scaffolds. Chemical engineering strategies are herein reported including host-guest inclusion complexation and covalent linkages. It also offers descriptions of the MRI properties and in vitro and in vivo biomedical applications of these emerging macrostructures. It highlights that these supramolecular associations can improve the image contrast, the sensitivity, and the efficiency of MRI diagnosis by targeting cancer tumors and other diseases with success proving the great potential of this natural macrocycle.

A versatile and recyclable molecularly imprinted polymer as an oxidative catalyst of sulfur derivatives: a new possible method for mustard gas and V nerve agent decontamination.

A molecularly imprinted polymer containing a porphyrin unit was developed as a biomimetic heterogenous catalyst for the oxidation of sulfur derivatives. Its catalytic efficiency under mild conditions and its easy recovery represent a great asset for the design of new decontamination tools for yperite and VX.

Heterogeneous-phase Sonogashira cross-coupling reaction on COC surface for the grafting of biomolecules - Application to isatin.

The grafting of 5-iodoisatin heterocycle on a cyclic olefin copolymer (COC) and a gold surface was performed using a heterogeneous phase Sonogashira reaction consisting of coupling 5-iodoisatin with an arylalkyne previously introduced onto the surfaces. This optimized strategy takes advantage of the well-established methodology to functionalize COC or gold surfaces using aryldiazonium surface chemistry. Herein, we reported the first example of an isatin decorated polymeric or metallic surface. The surfaces were analyzed with a combination of techniques such as IR (Infrared spectroscopy), XPS (X-Ray photoelectron spectroscopy) and SPR (surface plasmon resonance). Docking studies showed that isatin and two derivatives interact with AmiC, a dimeric protein produced by Pseudomonas aeruginosa. Bacterial adhesion on isatin-COC platform was also observed. This general strategy for robust surface functionalization represents an easy approach for patterning surfaces with compounds of biological interest, allowing access to a large panel of original biosensors.

Effect of the Incorporation of Functionalized Cyclodextrins in the Liposomal Bilayer.

Liposomes loaded with drug­cyclodextrin complexes are widely used as drug delivery systems, especially for species with low aqueous solubility and stability. Investigation of the intimate interactions of macrocycles with liposomes are essential for formulation of efficient and stable drug-in-cyclodextrin-in-liposome carriers. In this work, we reported the preparation of unilamellar vesicles of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) embedded with native ß-cyclodextrin and two synthetic derivatives: heptakis(2,3,6-tri-O-methyl)-ß-cyclodextrin (TMCD) and heptakis(2,3-di-O-acetyl)-ß-cyclodextrin (DACD). We then studied the effect of these macrocycles on the liposomal size, membrane viscosity, and liposomal stability at different temperatures and concentrations. We observed that TMCD and DACD affected vesicle size and the change of size was related to CD concentration. Irrespective of its nature, the macrocycle established interactions with the phospholipidic head groups, preventing cyclodextrins to diffuse into the lipid bilayer, as confirmed by molecular dynamics simulations. Such supramolecular structuring improves liposome stability making these colloid systems promising carriers for biologically active compounds.

Structure-efficiency relationships of cyclodextrin scavengers in the hydrolytic degradation of organophosphorus compounds.

New derivatives of cyclodextrins were prepared in order to determine the relative importance of the structural key elements involved in the degradation of organophosphorus nerve agents. To avoid a competitive inclusion between the organophosphorus substrate and the iodosobenzoate group, responsible for its degradation, the latter group had to be covalently bound to the cyclodextrin scaffold. Although the presence of the α nucleophile iodosobenzoate was a determinant in the hydrolysis process, an imidazole group was added to get a synergistic effect towards the degradation of the agents. The degradation efficiency was found to be dependent on the relative position of the heterocycle towards the reactive group as well as on the nature of the organophosphorus derivative.

Interactions of cyclodextrins and their derivatives with toxic organophosphorus compounds.

The aim of this review is to provide an update on the current use of cyclodextrins against organophosphorus compound intoxications. Organophosphorus pesticides and nerve agents play a determinant role in the inhibition of cholinesterases. The cyclic structure of cyclodextrins and their toroidal shape are perfectly suitable to design new chemical scavengers able to trap and hydrolyze the organophosphorus compounds before they reach their biological target.

New modified ß-cyclodextrin derivatives as detoxifying agents of chemical warfare agents (II). In vitro detoxification of cyclosarin (GF): general screening and toxicokinetic aspects of OP scavengers.

As standard therapy of intoxication with organophosphorus (OP) compounds is still insufficient, developing new treatment strategies is urgently required. For evaluating potential of OP detoxification of several compounds correctly, different toxicodynamic impact of OP enantiomers has to be considered thoroughly. It has already been demonstrated that ß-cyclodextrin (ß-CD) derivatives with attached nucleophilic substituent iodosobenzoic acid (IBA) can be regarded as potent OP scavengers due to an accelerating effect on decay of different OP. Herein, six CD derivatives permethylated or not on CD torus as well as differently attached nucleophilic substituent IBA derivative were investigated regarding detoxification of GF as an OP model substance. Acceleration of GF detoxification could be detected for all compounds with highest rate constants for propylene chain linked nucleophilic substituents on CD derivative. In addition, fast initial binding of GF on CD could be observed and is ascribed to formation of CD complexes. Furthermore, terminal plateau phase was detected of about 1% of each enantiomer reflecting the necessity of a quantitative determination at low concentrations. Moreover, this molecular depot formation may represent an additional detoxification pathway for OP.

New modified ß-cyclodextrin derivatives as detoxifying agents of chemical warfare agents (I). Synthesis and preliminary screening: evaluation of the detoxification using a half-quantitative enzymatic assay.

Current treatments of organophosphorus nerve agents poisoning are imperfect, and more efficient medical countermeasures need to be developed. Chemical scavengers based on ß-cyclodextrin displayed promising results, but further investigations have to be performed to evaluate the possibility of application of substituted cyclodextrins as potential detoxification agents. Herein, five new cyclodextrins scavengers were synthesized. New optimal conditions for regioselectively monosubstitution of ß-cyclodextrin at O-2 position were then studied to access to key intermediates. After these optimizations, a new series of three permethylated derivatives was developed, and two compounds bearing an α-nucleophilic group via a three carbon atoms linker were prepared. The ability of these five scavengers to detoxify nerve agents (cyclosarin, soman, tabun and VX) was evaluated by a semi-quantitative biological assay. All the modified cyclodextrins significantly decreased the inhibitory effect of chemical warfare G agents on acetylcholinesterase activity. For this purpose, we showed that the specific interactions between the organophosphorus compound and the oligosaccharidic moiety of the scavenger played a pivotal role in the detoxification process.

Optimized strategies to synthesize ß-cyclodextrin-oxime conjugates as a new generation of organophosphate scavengers.

A new generation of organophosphate (OP) scavengers was obtained by synthesis of ß-cyclodextrin-oxime derivatives 8-12. Selective monosubstitution of ß-cyclodextrin was the main difficulty in order to access these compounds, because reaction onto the oligosaccharide was closely related to the nature of the incoming group. For this purpose, non-conventional activation conditions were also evaluated. Intermediates 5 and 7 were then obtained with the better yields under ultrasounds irradiation. Finally, the desired compounds 8-10 were obtained from 5-7 in high purity by desilylation using potassium fluoride. Quaternarisation of compounds 8 and 9 was carried out. OP hydrolytic activity of compounds 8-12 was evaluated against cyclosarin (GF) and VX. None of the tested compounds was active against VX, but these five cyclodextrin derivatives detoxified GF, and the most active scavengers 10 and 11 allowed an almost complete hydrolysis of GF within 10 min. Even more fascinating is the fact that compounds 9 and 10 were able to hydrolyze enantioselectively GF.

In vitro detoxification of cyclosarin (GF) by modified cyclodextrins.

Developing potent detoxification strategies for prophylaxis and therapy against organophosphate (OP) intoxication still represents a challenging task. Clinical application of numerous investigated substances including enzymes and low molecular scavengers like metal ions or nucleophiles could not yet be realised due to profound disadvantages. Presenting a promising attempt, cyclodextrins (CDs) efficiently enhance the degradation of some organophosphorus compounds. The present study examined the in vitro GF degradation mediated by three CDs and a nucleophilic precursor performed by mass spectrometric detection with ammonia chemical ionisation. All four compounds caused a notable enhancement of GF detoxification that was synergistically accelerated in the case of 2-O-(3-carboxy-4-iodosobenzyl)-ß-cyclodextrin (IBA-ß-CD) with the alpha-nucleophile 2-iodosobenzoic acid (IBA) grafted on the secondary face of ß-cyclodextrin (ß-CD). In vitro toxicokinetic investigations of CD derivatives are needed to evaluate the effect of slow terminal elimination phase of the more toxic (-)-GF shown for two CD-derivatives underlining the necessity of detecting the complete kinetic course of inactivation. The observed effect of fast high affinity binding (20-30%) represents an additional therapeutic option of an extremely rapid reduction of GF concentration in vivo. Distinctive differences in the course of reaction are detected depending on ß-CD-derivatives, allowing a first inference of possible mechanisms and relevance of attached substituents. However, further profound investigation needs to be done to evaluate the basis of a clinical application of substituted CDs as potential detoxification agents.

Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ.

The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect.

Regioselective access to 3I-O-substituted-beta-cyclodextrin derivatives.

Formation of a copper(ii)-beta-cyclodextrin (beta-CD) complex in an aqueous medium allowed the regioselective introduction into the oligosaccharide of a benzyl or a bromo-allyl substituent at O-3.

Investigation of N-hydroxythalidomide in vitro stability and comparison to other N-substituted derivatives.

The stability of N-substituted derivatives of thalidomide was studied and compared to that of thalidomide itself. Nitrogen atom included in glutarimide ring was successively substituted by a hydroxy group, a methyl acetate group, and an ethyl group. Lipophilicities of these compounds were determined using the method based on experimental determinations of partition coefficients developed by Hansch. Hydroxy group led to a decrease of lipophilicity. Substitution of the nitrogen atom by an ethyl group or a methyl acetate group allowed an increase of lipophilicity. Relative stabilities of each compound were determined under physiological conditions: pH (7.4) and temperature (37 degrees C) using high performance liquid chromatography procedure. The program Sigma Plot was used to fit experimental data in order to obtain the half-lifes of thalidomide and its analogs. In the case of substitution by an ethyl group, the increase of lipophilicity (Delta log P = 0.36) was in agreement with a higher stability in aqueous medium. In the case of methyl acetate group, hydrolysis of the cycle was chemically favoured despite a higher lipophilicity compared to those of thalidomide. In the case of N-hydroxy compound, the decrease in lipophilicity was not sufficient to affect the stability.

Improved access to 2-O-monobenzyl ethers of beta-cyclodextrin as precursors of catalysts for organophosphoryl esters hydrolysis.

A comparative study of reaction conditions was performed for the synthesis of a 2-O-monobenzyl ether of cyclomaltoheptaose (beta-CD). Optimal conditions involved sodium ethoxide in Me(2)SO and benzyl bromide. The methodology was extended to the preparation of various 2(I)-O-iodobenzyl and 2(I)-O-carboxymethylbenzyl derivatives of beta-CD including a 3-carboxymethyl-4-iodobenzyl derivative of interest as precursor of an enzyme mimic to degrade the organophosphoryl ester diethyl 4-nitrophenyl phosphate (paraoxon).

Synthesis of 2-substituted beta-cyclodextrin derivatives with a hydrolytic activity against the organophosphorylester paraoxon.

Beta-cyclodextrin was substituted by an iodosobenzoic acid derivative to create a catalytic hydrolytic activity against neurotoxic organophosphorus agents. The catalytic moiety was introduced on a secondary hydroxy group at the position 2 of a glucose unit. Several beta-cyclodextrin derivatives were obtained. In these derivatives, the methylene linker occupied all potential positions on the aromatic ring. Kinetic assays were carried out with paraoxon as organophosphate model. Three regioisomers hydrolyzed paraoxon, although the paraoxon-leaving group, para-nitrophenol, was not released from the beta-cyclodextrin torus.

Regio- and diastereocontrolled preparative oxidation of methyloctalones by a biomimetic porphyrin catalyst.

Both enantiomers of methyloctalone were oxidized by a biomimetic manganese/porphyrin/imidazole catalytic system in order to obtain sufficient amounts of various model metabolites. The double bond proved to be less sensitive than the ring methylenes. Hydroxylation occurred mainly in the allylic position (position 8) and also at positions 7 and 6. In position 8, two diastereomers were obtained while in positions 7 and 6 the reaction was diastereospecific. In the case of position 8 only the oxidation yielded a keto compound. The efficiency of this method for the preparation of functionalized chiral synthons was better than it was for biological pathways.

Comparison of the efficiency of various methods for the synthesis of models of metabolites: example of 4a-methylhexahydronaphtalenones.

In order to examine the biotransformations of xenobiotics, it is essential to realize studies of metabolism of drugs in living animals. It is generally difficult to extract quantitatively the metabolites from biological media or excreta. Alternative methods have then been developed. Application of such techniques to 4a-methylhexahydronaphthalenones, which constitute starting material for the stereospecific synthesis of terpenoids or steroids, is particularly demonstrative. By biosynthetical ways, it was not possible to access with good yields to all the metabolites obtained in vivo. A novel methodology, based on the use of a manganoporphyrin catalyst, allowed to synthesize large amounts of several models of metabolites corresponding to those which had been isolated in living rats. Only one of the metabolites obtained in vivo could not be synthesized by this biomimetic system. This proved that alternative methods are precious to obtain models with good yields, but need to be validated by controls in living animals.

Improvement of a biomimetic porphyrin catalytic system by addition of acids.

The conditions of the use of the manganese/porphyrin/imidazole system needed to be improved in order to obtain larger amounts of models of metabolites. An increase of the oxidation yields and a better preservation of this catalytic system have been obtained on the examples of various alkanes, by an acid addition in the reaction mixture. Three manganoporphyrins were checked for evaluation of the reaction. These results were extended to molecules of therapeutical interest such as ibuprofen and phenylbutazone.