Synthèse asymétrique du système polycyclique oxygéné du (+)-harringtonolide

L harringtonolide, est un norditerpène polycyclique complexe isolé pour la première fois en 1978 des drupes de Cephalotaxus harringtonia. Cet arbre asiatique que l on peut d ailleurs voir au Jardin des Plantes du Muséum National d Histoire Naturelle est utilisé en médecine traditionnelle chinoise contre la leucémie. Cette utilisation a suscité l intérêt des chimistes pour les molécules extraites de cet arbre. Ainsi il a été prouvé que l harringtonolide possède des activités antivirale et anti-tumorale, ou d inhibition de la croissance végétale. De plus, cette molécule possède une structure originale qui n a été observée que pour quatre autres molécules de la même famille. Toutes ces raisons nous ont amenée à envisager la synthèse de cette molécule sachant qu aucune synthèse asymétrique n a été, jusqu à présent, rapportée. Nous nous sommes alors fixés une stratégie à 5 objectifs au départ du D-glucose, porteur de la chiralité, et passant par plusieurs étapes clés indispensables à la formation du cycle A, puis du cycle D, du pont oxygéné et enfin des cycles B et C. Le cycle A sera introduit grâce à une cyclisation de Diels-Alder intramoléculaire et stéréocontrôlée, le cycle D grâce à une fermeture de cycle par métathèse d un 1,6-diène, les cycles oxygénés grâce à une réaction en cascade d inspiration biomimétique, et enfin le cycle tropone C sera construit grâce à une cycloaddition [5+2]. Ce travail décrit la synthèse asymétrique du système oxygéné polycyclique du (+)-harringtonolide ainsi que les études préliminaires effectuées autour de la méthodologie de cycloaddition [5+2] en vue de la génération du cycle tropone CHarringtonolide, is a complex polycyclic norditerpene, isolated for the first time in 1978 by the Asian plum yew Cephalotaxus harringtonia. This Asian tree - that we can see in the Jardin des Plantes of the National Museum of Natural History in Paris- is used in Chinese traditional medicine against leukaemia. This use aroused the interest of chemists for molecules extracted from this tree. It was proved that harringtonolide possesses interesting biological activities such as antiviral and anti-tumoral activity or inhibition of the vegetable growth. Furthermore, this molecule possesses an original structure which was observed only for four other molecules of the same family. All these reasons brought to us to envisage the synthesis of this molecule knowing that no asymmetric synthesis was, until now, reported. We then settled a strategy in 5 objectives from D-glucose, molecule bringing the asymmetry, and going through several key steps indispensable to the formation of the cycle A, then the cycle D, the oxygenated ring system and finally the cycles B and C. The cycle A will be introduced thanks to an intramolecular and stereocontrolled Diels-Alder cyclisation, the cycle D thanks to a ring closing metathesis of a 1,6-diene, the oxygenated ring system thanks to a cascade initiated by an epoxide opening, and finally the tropone C will be constructed thanks to a [5+2] cycloaddition. This work describes the asymmetric synthesis of the oxygenated polycyclic system of (+)-harringtonolide as well as the preliminary studies made around the methodology of [5+2] cycloaddition, with the aim of the generation of the cycle tropone C.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Regioselective Halogenation of 1,4-Benzodiazepinones via CH Activation

International audienceThis article reports an efficient CH activation process for regioselective halogenation of 1,4-benzodiazepinones. Direct halogenation with NXS (X = Br, I) affords halogenated benzodiazepinones on the central aromatic ring whereas catalyst (Pd(OAc) 2) controlled CH activation furnishes regioselectively ortho halogenated benzodiazepinones on the phenyl side chain

Asymmetric Synthesis of the Oxygenated Polycyclic System of (+)-Harringtonolide

A straightforward asymmetric synthesis of the cage oxygenated structure of (+)-harringtonolide has been accomplished for the first time. The key steps involved (i) a templated stereoselective IMDA reaction to build a highly functionalized cyclohexene ring D, (ii) functionalization of the cycloadduct, (iii) ring-closing metathesis providing the five-membered ring C, and finally (iv) a challenging one-step cascade cyclization of an epoxy-alcohol toward the target structure, whose mechanism was investigated

Asymmetric Synthesis of the Oxygenated Polycyclic System of (+)-Harringtonolide

A straightforward asymmetric synthesis of the cage oxygenated structure of (+)-harringtonolide has been accomplished for the first time. The key steps involved (i) a templated stereoselective IMDA reaction to build a highly functionalized cyclohexene ring D, (ii) functionalization of the cycloadduct, (iii) ring-closing metathesis providing the five-membered ring C, and finally (iv) a challenging one-step cascade cyclization of an epoxy-alcohol toward the target structure, whose mechanism was investigated

Effect of heavy metals mixture on the growth and physiology of Tetraselmis sp.: Applications to lipid production and bioremediation

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Flow cytometry assay to evaluate lipid production by the marine microalga Tetraselmis sp. using a two stage process

International audienceTetraselmis sp. strain MD-01, a microalga isolated from the Tunisian marine coast, has been studied for autotrophic lipids production with two stage process. This strategy was conducted for maximum cells production under moderated conditions (2.12 g L−1), followed by cultivation under stressed conditions to induce lipid synthesis. High irradiance (300 μmol m−2 s−1) and nitrogen depletion (S mode) showed better carotenoids accumulation and lower chlorophylls content in microalgae compared to those obtained in biomass cultivated under high irradiance (Sg mode). This two-stage strategy allowed to increase of lipid content in cells cultivated in Sg and S modes from 18% DW (stage I) to 50 and 61.5% DW (stage II), respectively, with an increase of saturated and long chain fatty acids levels. Based on fluorometry analyses, an increase of lipids in Nile-Red stained cells and a decrease of chlorophylls auto-fluorescence under stressed conditions were shown. From spectral data, the lipids: amide I ratio obtained from S mode was 2.17 and 4.45 times higher than that from Sg mode and control conditions, respectively. These results revealed the potential of Tetraselmis strain MD-01 for biodiesel production

Microalgae: A Promising Source of Bioactive Phycobiliproteins

Phycobiliproteins are photosynthetic light-harvesting pigments isolated from microalgae with fluorescent, colorimetric and biological properties, making them a potential commodity in the pharmaceutical, cosmetic and food industries. Hence, improving their metabolic yield is of great interest. In this regard, the present review aimed, first, to provide a detailed and thorough overview of the optimization of culture media elements, as well as various physical parameters, to improve the large-scale manufacturing of such bioactive molecules. The second section of the review offers systematic, deep and detailed data about the current main features of phycobiliproteins. In the ultimate section, the health and nutritional claims related to these bioactive pigments, explaining their noticeable potential for biotechnological uses in various fields, are examined

Carotenoids Overproduction in Dunaliella Sp.: Transcriptional Changes and New Insights through Lycopene β Cyclase Regulation

Dunaliella is a green microalga known for its ability to produce high levels of carotenoids under well-defined growing conditions. Molecular responses to the simultaneous effect of increasing salinity, light intensity and decrease of nitrogen availability were investigated in terms of their effect on different metabolic pathways (isoprenoids synthesis, glycolysis, carbohydrate use, etc.) by following the transcriptional regulation of enolase (ENO), 1-deoxy-D-xylulose 5-phosphate synthase (DXS), lycopene β-cyclase (LCYB), carotene globule protein (CGP), chloroplast-localized heat shock protein (HSP70), and chloroplast ribulose phosphate-3-epimerase (RPE) genes. The intracellular production of carotenoid was increased five times in stressed Dunaliella cells compared to those grown in an unstressed condition. At transcriptional levels, ENO implicated in glycolysis, and revealing about polysaccharides degradation, showed a two-stage response during the first 72 h. Genes directly involved in β-carotene accumulation, namely, CGP and LCYB, revealed the most important increase by about 54 and 10 folds, respectively. In silico sequence analysis, along with 3D modeling studies, were performed to identify possible posttranslational modifications of CGP and LCYB proteins. Our results described, for the first time, their probable regulation by sumoylation covalent attachment as well as the presence of expressed SUMO (small ubiquitin-related modifier) protein in Dunaliella sp

Apigenin analogues as SARS-CoV-2 main protease inhibitors: In-silico screening approach

International audienceThe COVID-19 new variants spread rapidly all over the world, and until now scientists strive to find virus-specific antivirals for its treatment. The main protease of SARS-CoV-2 (Mpro) exhibits high structural and sequence homology to main protease of SARS-CoV (93.23% sequence identity), and their sequence alignment indicated 12 mutated/variant residues. The sequence alignment of SARS-CoV-2 main protease led to identification of only one mutated/variant residue with no significant role in its enzymatic process. Therefore, Mpro was considered as a high-profile drug target in anti-SARS-CoV-2 drug discovery. Apigenin analogues to COVID-19 main protease binding were evaluated. The detailed interactions between the analogues of Apigenin and SARS-CoV-2 Mpro inhibitors were determined as hydrogen bonds, electronic bonds and hydrophobic interactions. The binding energies obtained from the molecular docking of Mpro with Boceprevir, Apigenin, Apigenin 7-glucoside-4’-p-coumarate, Apigenin 7-glucoside-4’-trans-caffeate and Apigenin 7-O-beta-d-glucoside (Cosmosiin) were found to be −6.6, −7.2, −8.8, −8.7 and −8.0 kcal/mol, respectively. Pharmacokinetic parameters and toxicological characteristics obtained by computational techniques and Virtual ADME studies of the Apigenin analogues confirmed that the Apigenin 7-glucoside-4’-p-coumarate is the best candidate for SARS-CoV-2 Mpro inhibition