Efficient synthesis of small-sized phosphonated dendrons: potential organic coatings of iron oxide nanoparticles:

We report herein the synthesis of biocompatible small-sized phosphonated monomers and dendrons used as functional coatings of metal oxide nanoparticles, more specifically superparamagnetic iron oxides (SPIOs) for magnetic resonance imaging (MRI) and therapy through hyperthermia. The molecules were engineered to modulate their size, their hydrophilic and/or biocompatible character (poly(amido) amine versus oligoethyleneglycol), the number of anchoring phosphonate groups (monophosphonate versus phosphonic tweezers) and the number of peripheral functional groups for further grafting of dyes or specific vectors. Such a library of hydrophilic phosphonic acids opens new possibilities for the investigation of dendronized nanohybrids as theranostics

Direct intramolecular aldolization organocatalyzed by guanidines and application to the total synthesis of Nigellamine A

L'organocatalyse est largement reconnue aujourd hui comme étant une des plus importantes branches de la synthèse asymétrique, avec la catalyse enzymatique et métallique. Ainsi, dans le cadre de la synthèse totale de la Nigellamine A dont la rétrosynthèseToday, organocatalysis is one of the most important branches of the asymmetric synthesis along with the enzymatic and the metallic catalysis. We were particularly interested in this field while developing a retrosynthesis of a natural product, the Nigell

Direct intramolecular aldolization organocatalyzed by guanidines and application to the total synthesis of Nigellamine A

L'organocatalyse est largement reconnue aujourd hui comme étant une des plus importantes branches de la synthèse asymétrique, avec la catalyse enzymatique et métallique. Ainsi, dans le cadre de la synthèse totale de la Nigellamine A dont la rétrosynthèse repose sur une étape clé, l'aldolisation intramoléculaire directe d'un cétoaldéhyde acyclique fonctionnalisé, nous nous sommes intéressés à l'organocatalyse pour le développement d'une méthode de cyclisation chimiosélective afin d'accéder au cétol désiré. Ainsi, une première partie des travaux repose sur le développement et l'utilisation des guanidines comme organocatalyseurs dans la réaction d'aldolisation intramoléculaire directe. Une étude systématique et conséquente a permis de mettre au point une nouvelle méthodologie permettant d'obtenir des cétols à partir de cétoaldéhydes avec une excellente chimiosélectivité et de très bons rendements. Dans une deuxième partie, nous avons appliqué la méthodologie à la synthèse totale de la Nigellamine A, une molécule présentant des propriétés hypolipidémiques intéressantes. La cyclisation n a pas été aussi chimiosélective et la purification du cétol obtenu par chromatographie sur gel de silice a posé problème et reste à optimiser. En parallèle, nous avons également utilisé les guanidines chirales comme catalyseurs d'acétylation énantiosélective, pour la résolution cinétique d'amines. Finalement, la dernière partie aborde une nouvelle méthodologie mise au point pour la synthèse de buténolides a-alkylés, composés communs de nombreux produits naturels importants et son application à la synthèse totale du (+)-Ancepsenolide.Today, organocatalysis is one of the most important branches of the asymmetric synthesis along with the enzymatic and the metallic catalysis. We were particularly interested in this field while developing a retrosynthesis of a natural product, the Nigellamine A. In fact, the key step relies on a direct intramolecular aldol reaction of an acyclic ketoaldehyde. We therefore developed and used guanidines as potential organocatalysts for this transformation. A consequent study allowed the formation of ketol compounds from ketoaldehydes with excellent chemoselectivity and good yields. We then applied this methodology to the total synthesis of the Nigellamine A, an active compound with hypolipidemic properties. The cyclization was not as chemoselective as expected and the purification of the desired ketol by silica gel chromatography was not efficient and needs to be optimized. In parallel, we also used chiral guanidines as catalysts for the enantioselective acetylation of amines. Finally, the last part highlights a new methodology developed for the synthesis of a-alkylated butenolids, important precursors for many natural products, and its application to the total synthesis of (+)-Ancepsenolide

Aldolisation intramoléculaire directe organocatalysée par les guanidines et application à la synthèse totale de la Nigellamine A

L organocatalyse est largement reconnue aujourd hui comme étant une des plus importantes branches de la synthèse asymétrique, avec la catalyse enzymatique et métallique. Ainsi, dans le cadre de la synthèse totale de la Nigellamine A dont la rétrosynthèse repose sur une étape clé, l aldolisation intramoléculaire directe d un cétoaldéhyde acyclique fonctionnalisé, nous nous sommes intéressés à l organocatalyse pour le développement d une méthode de cyclisation chimiosélective afin d acce der au cétol désiré. Ainsi, une première partie des travaux repose sur le développement et l utilisation des guanidines comme organocatalyseurs dans la réaction d aldolisation intramoléculaire directe. Une étude systématique et conséquente a permis de mettre au point une nouvelle méthodologie permettant d obtenir des cétols à partir de cétoaldéhydes avec une excellente chimiosélectivité et de très bons rendements. Dans une deuxième partie, nous avons appliqué la méthodologie à la synthèse totale de la Nigellamine A, une molécule présentant des propriétés hypolipidémiques intéressantes. La cyclisation n a pas été aussi chimiosélective et la purification du cétol obtenu par chromatographie sur gel de silice a posé problème et reste à optimiser. En parallèle, nous avons également utilisé les guanidines chirales comme catalyseurs d acétylation énantiosélective, pour la résolution cinétique d amines. Finalement, la dernière partie aborde une nouvelle méthodologie mise au point pour la synthèse de buténolides a-alkylés, composés communs de nombreux produits naturels importants et son application à la synthèse totale du (+)-Ancepsenolide.Today, organocatalysis is one of the most important branches of the asymmetric synthesis along with the enzymatic and the metallic catalysis. We were particularly interested in this field while developing a retrosynthesis of a natural product, the Nigellamine A. In fact, the key step relies on a direct intramolecular aldol reaction of an acyclic ketoaldehyde. We therefore developed and used guanidines as potential organocatalysts for this transformation. A consequent study allowed the formation of ketol compounds from ketoaldehydes with excellent chemoselectivity and good yields. We then applied this methodology to the total synthesis of the Nigellamine A, an active compound with hypolipidemic properties. The cyclization was not as chemoselective as expected and the purification of the desired ketol by silica gel chromatography was not efficient and needs to be optimized. In parallel, we also used chiral guanidines as catalysts for the enantioselective acetylation of amines. Finally, the last part highlights a new methodology developed for the synthesis of a-alkylated butenolids, important precursors for many natural products, and its application to the total synthesis of (+)-Ancepsenolide.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Synthesis of Hydrophobic Carbohydrate Polymers and Their Formation of Thermotropic Liquid Crystalline Phases

The first synthesis of enantiopure glucose octyl ether polyamido-saccharides (GOE-PAS) with a defined molecular weight and narrow dispersity is reported using a controlled anionic ring-opening polymerization of a glucose-derived β-lactam sugar monomer possessing octyl ether chains. This new polymer structure is characterized by NMR, infrared (IR), optical rotation, gel permeation chromatography (GPC), and thermogravimetric analysis (TGA). At room temperature, the polymers form lamellar (Lam) phases. Upon heating to mild temperatures (ca. 60 °C), the shortest polymer shows a direct transition to the isotropic (Iso) liquid state, while the longer polymers give rise to a hexagonal columnar (Col_h) phase before becoming isotropic at higher temperatures (ca. 120 °C)

Cloning, Purification, and Characterization of a β-Carbonic Anhydrase from <i>Malassezia restricta</i>, an Opportunistic Pathogen Involved in Dandruff and Seborrheic Dermatitis

The cloning, purification, and initial characterization of the &#946;-carbonic anhydrase (CA, EC 4.2.1.1) from the genome of the opportunistic pathogen Malassezia restricta (MreCA), which a fungus involved in dandruff and seborrheic dermatitis (SD), is reported. MreCA is a protein consisting of 230 amino acid residues and shows high catalytic activity for the hydration of CO2 into bicarbonate and protons, with the following kinetic parameters: kcat of 1.06 &#215; 106 s&#8722;1 and kcat/KM of 1.07 &#215; 108 M&#8722;1 s&#8722;1. It is also sensitive to inhibition by the sulfonamide acetazolamide (KI of 50.7 nM). Phylogenetically, MreCA and other CAs from various Malassezia species seem to be on a different branch, distinct from that of other &#946;-CAs found in fungi, such as Candida spp., Saccharomyces cerevisiae, Aspergillus fumigatus, and Sordaria macrospora, with only Cryptococcus neoformans and Ustilago maydis enzymes clustering near MreCA. The further characterization of this enzyme and the identification of inhibitors that may interfere with its life cycle might constitute new strategies for fighting dandruff and SD

The efficacy of a lysine-based dendritic hydrogel does not differ from those of commercially available tissue sealants and adhesives: an ex vivo study

Background: Hemostatic agents, tissue adhesives and sealants may contribute to a reduction in hemorrhage-associated morbidity and mortality. Towards this end, we have recently developed a lysine-based dendritic hydrogel (PEG-LysNH2) that can potentially be used in the management of severe trauma and/or intraoperative bleeding. As a first step in demonstrating the potential utility of this approach, our objective was to ascertain the ability of the PEG-LysNH2 to adhere to and seal injured tissues, as well as to maintain the seal under physiological conditions. Methods: The efficacy of the PEG-LysNH2 in sealing injured tissues was evaluated using an ex-vivo pressure testing system. A 2.5 mm incision was made on intact ex-vivo tissues and then sealed with the PEG-LysNH2. Application of the PEG-LysNH2 was followed by 1) step-wise pressure increase to a maximum of 250 mmHg and 2) fluctuating pressures, between 100–180 mmHg with a rate of 3 Hz, over a 24-hour period. The performance of the PEG-LysNH2 was compared to those of commercially available sealants and adhesives. Results: During gradual pressure increase, mean pressures at 30 seconds (P30) ranged between 206.36 - 220.17 mmHg for the sealants, and they were greater than control and suture groups (p < 0.01 and p = 0.013, respectively). Additionally, all products held under fluctuating pressures: mean pressures ranged between 135.20 - 160.09 mmHg, and there were no differences observed between groups (p = 0.96). Conclusions: The efficacy of the PEG-LysNH2 was significantly superior to conventional injury repair methods (sutures) and did not differ from those of commercially available products when sealing small incisions

A bisphosphonate tweezers and clickable PEGylated PAMAM dendrons for the preparation of functional iron oxide nanoparticles displaying renal and hepatobiliary elimination

International audienceThe functionalization of superparamagnetic iron oxide nanoparticles (SPION) with PEGylated PAMAM dendrons through a bisphosphonate tweezers yielded 15 and 30 nm dendritic nano-objects stable in physiological media and showing both renal and hepatobiliary elimination

Synthesis of Dendritic Nano-objects Dedicated to Horizontal Gene Transfer Between Bacteria in Soil Pollutant Bio-attenuation Processes

International audienceSuperparamagnetic iron-oxide nanoparticles (SPION) with tailored surface chemistry have recently attracted a great deal of attention for their potential biomedical applications including magnetic resonance imaging (MRI) contrast enhancement, tissue repair, immunoassay, detoxification of biological fluids, hyperthermia, drug and gene delivery, cell separation and magnetic-field-assisted radionuclide therapy. Our work is aimed at developing a new technology for the magnetic manipulation of bacterial cells marked with specific DNA onto which magnetic nanoparticles have been grafted. With this technology, it will be possible to selectively remove from the indigenous microbial population of a soil the bacteria that have been transformed with this magnetic DNA. The tagging of plasmids comprising genes involved in chlorous pollutant degradation pathway will enable to understand the horizontal gene transfer mechanisms involved in the eviction of hard-to-remove polluants such as Lindane. A dentritic approach for the decoration of the nanoparticles appears promising as the diversity of functionalization brought by the arborescent structure answers simultaneously all the criteria of biocompatibility, low toxicity and specificity. The structure of the proposed dendritic molecules can be divided into 3 parts: a biphosphonate group at the core which allows a strong and stable coupling between the nanoparticle and the dendritic part under various pH and temperature conditions, a PAMAM (polyaminoamine)-derived dendron and then, at the periphery, hydrophilic and biocompatible oligoethyleneglycol chains decorated with arnino or carboxylic groups, allowing an interaction with the DNA through phosphate or arnine groups. It IlUlst be noted that the synthetic organic shell is easily tunable and allows the conjugation of various parts (PAMAM efficiency in DNA-complexation; OEG hydro-soluble and non toxic) in order to associate their advantages. The dentritic approach, compared to the polymeric one, allows a better size control of the decorated nanoparticles (as a function of the generation of the grafted dendron), a better follow-up of the DNA binding properties (as a function of the generation and the physico-chemical properties of the dendrimer) and finally an ensured reproductibility. The synthesis of the dentritic organic shell, its functionalization on iron oxide nanoparticles and their characterization will be presented

Activation studies of the β-carbonic anhydrases from Malassezia restricta with amines and amino acids

The β-carbonic anhydrase (CA, EC 4.2.1.1) from the genome of the opportunistic pathogen Malassezia restricta (MreCA), which was recently cloned and characterised, herein has been investigated for enzymatic activation by a panel of amines and amino acids. Of the 24 compounds tested in this study, the most effective MreCA activators were L-adrenaline (KA of 15 nM), 2-aminoethyl-piperazine/morpholine (KAs of 0.25–0.33 µM), histamine, L-4-amino-phenylalanine, D-Phe, L-/D-DOPA, and L-/D-Trp (KAs of 0.32 − 0.90 µM). The least effective activators were L-/D-Tyr, L-Asp, L-/D-Glu, and L-His, with activation constants ranging between 4.04 and 12.8 µM. As MreCA is involved in dandruff and seborrhoeic dermatitis, these results are of interest to identify modulators of the activity of enzymes involved in the metabolic processes of such fungi