Synthèse d'hybrides vinblastine-phomopsine.

La tubuline est une protéine essentielle de la cellule. En polymérisant sous forme de microtubules, elle crée notamment le fuseau mitotique le long duquel migrent les chromosomes pendant la mitose. Les médicaments qui inhibent la polymérisation et/ou la dépolymérisation de la tubuline sont des composés majeurs de la thérapie anticancéreuse. Les vinca-alcaloïdes en sont des représentants importants. Ils induisent la mort des cellules par apoptose, en inhibant la dynamique des microtubules. D autres molécules d origine naturelle, comme la phomopsine A, se fixent sur la tubuline à proximité ou dans le même site de fixation que celui des vinca-alcaloïdes. C est la raison pour laquelle nous avons envisagé d élaborer des composés antimitotiques hybrides entre la vinblastine et la phomopsine A. Dans ce contexte, deux séries de composés ont été conçues. La première série d hybrides correspondant à des dérivés de l anhydrovinblastine fonctionnalisés en position 7 . Cependant, aucune des trois stratégies étudiées n a permis d accéder à ces composés. La deuxième série d hybrides, dérivés de la 7 -homo-anhydrovinblastine a pu être synthétisée grâce à une réaction originale d insertion d acétylènes activés au niveau du pont gramine de la vinorelbine, suivie d une réduction avec un contrôle totale de la régio- et stéréoselectivité. Dans un premier temps, les réactions d insertion et de réduction ont été mise au point. Ensuite, deux familles d hybrides portant la chaîne latérale de l octahydrophomopsine en position 8 ou 7 ont été synthétisés. La plupart des composés ainsi obtenus possédent une excellente activité sur la tubuline et sont très cytotoxique.Tubulin plays a key role in many cellular functions, like cell division. Microtubules, resulting from its polymerisation, form the mitotic spindle along which chromosomes migrate during mitosis. Tubulin-binding molecules are one of the most important classes of anti-cancer agents with major drugs already on the market and many promising compounds in clinical trials. Vinca-alkaloids are one of these antimitotic drugs inhibiting microtubules dynamics. It was shown that the vinca binding site partially overlaps with that of others natural products, like phomopsin A. In order to explore the vinca domain and to elaborate new acute derivatives, we have elaborated antimitotic vinblastine-phomopsin hybrids. We were interested in the synthesis of two series of hybrids. The first, corresponding to 7 -anhydrovinblastine derivatives could not be obtained. None of the three studied strategies lead to desired compounds. The second series of hybrids, corresponding to functionnalized 7 -homo-anhydrovinblastine derivatives, could be synthetised by an original and regioselective insertion reaction, followed by a stereoselective reduction. Firstly, the isertion reaction was studied using different activated acetylenes. Then, two different families of hybrids were obtained, thanks to the selective insertion of the octahydrophomopsin lateral chain in position 8 or 7 . Almost all the compounds were highly active on tubulin and very cytotoxic.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Premières pharmacomodulations de la meiogynine A, un sesquiterpène dimère inhibiteur de l'interaction Bcl-xL/Bak, régulant l'apoptose

La régulation de l apoptose fait partie des nouvelles cibles thérapeutiques dans la lutte contre le cancer. L apoptose est l autodestruction programmée des cellules qui, suite à un besoin physiologique, permet de réguler le développement des cellules. Dans de nombreux cancers, ce mécanisme est inhibé par une surexpression des protéines anti-apoptotiques de la famille Bcl-2 comme Bcl-xL et Mcl-1. Ce phénomène entraîne le développement des cellules tumorales et des résistances aux chimiothérapies. Dans cette optique, notre équipe à l Institut de Chimie des Substances Naturelles a développé un criblage de plantes tropicales sur ces cibles. Des écorces d une annonacée de Malaisie, Meiogyne Cylindrocarpa, a été isolé un sesquiterpène dimère, la meiogynine A, présentant une bonne affinité vis-à-vis de Bcl-xL (Ki = 10.7 M). Sa synthèse totale a été réalisée au laboratoire afin de déterminer sa configuration absolue et d étudier les premières relations structure activité. Un de ses diastéréoisomères a également présenté une bonne affinité vis-à-vis de la protéine Bcl-xL.Afin d étudier et d approfondir les premières relations structure activité, la modulation de la meiogynine A a été réalisée. La synthèse des diénophiles acides a été optimisée afin de conduire majoritairement aux diénophiles précurseurs des composés actifs. Différents triènes ont également été synthétisés au laboratoire en vue de modifier la partie Sud de la meiogynine A. Plusieurs analogues ont ainsi pu être obtenus et ont été évalués biologiquement sur des tests in vitro et ex vivo. Des études de modélisation moléculaire et de RMN structurale ont également été réalisées.The control of the apoptosis is one of the new modern key to fight against the cancer. The apoptosis is the self destruction of cells, part of the homeostasis, which regulates the cell developement. In several cancers, the over-expression of anti-apoptotic proteins, as Bcl-xL and Mcl-1 parts of the Bcl-2 proteins family, inhibate this naturel process. This phenomenum induce the tumoral cells developement and the chemotherapy s resistance. In order to find new compounds which can regulate the apoptosis, our group in the Institut de Chimie des Substances Naturelles has screened different tropical plants on these targets. A Malaysian plant, Meiogynine Cylindrocarpa, was selected and the phyotchemist work on this plant gave us a new sesquiterpen , the meiogynin A (Ki = 10.7 M on Bcl-xL). Its total synthesis was realised in our laboratory in order to determine its absolute configuration and find the first structure activity relation. One of the synthetised diastereoisomers has presented a better affinity toward the protein. In order to precise these first structure activity relations, the modulation of the meiogynin A was initiated. The synthesis of the acid dienophiles was optimised, the main compounds are the precursors of the active decalins. New triene was also obtained in order to modulate the South Part of the meiogynin A. Thanks to a Diels-Alder reaction, these precursors were combined in order to form new analogues of the meiogynin A. All these compounds were biologically tested (in vitro et ex vivo). Experiments of molecular docking and 2D NMR were also realised.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Development of an efficient route toward meiogynin A-inspired dual inhibitors of Bcl-xL and Mcl-1 anti-apoptotic proteins

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Selectivity in the Intermolecular Diels-Alder Reaction of Conjugated Trienes: Experimental and Theoretical Approaches

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Elaboration of vinblastine hybrids using a reactive in situ generated N-carboxyanhydride.

International audienceHybrids of vinblastine and phomopsin, designed by a molecular modelling study, were elaborated in order to target tubulin. The key step of the synthesis (fragmentation and insertion of vindoline) was mediated by an internal N-carboxyanhydride (or O-acylcarbamate). This reaction was diastereospecific and addition of silver salts could reverse the diastereoselectivity. Even if the synthesized compounds are inactive, this synthesis represents an original example of a C-N fragmentation mediated by a N-carboxyanhydride

A Fast and Efficient MN-Approach for Reactivity of Natural Product Exploration in Plant Extract: Application to Diterpene Esters from Euphorbia dendroides

Natural products represent a rich source of bioactive compounds covering a large chemical space. Even if challenging, this diversity can be extended by applying chemical modifications. However, these studies require generally multigram amounts of isolated natural products and face frequent testing failures. To overcome this limitation, we propose a rapid and efficient approach that uses molecular networking (MN) to visualize new chemical diversity generated by simple chemical modifications of natural extract. Moreover, the strategy deployed enables the most appropriate reagents to be defined quickly upstream a reaction on a pure compound, in order to maximize chemical diversity. This methodology was applied to the latex extract of Euphorbia dendroides to follow the reactivity towards a series of acids and Lewis acids of three class of diterpene esters identified in this species: jatrophane, terracinolide, and phorbol. Through the molecular networking interpretation, in aim to illustrate our approach, two Lewis acids were selected for chemical modification on previously isolated jatrophane esters. Three rearranged compounds (3−5) were obtained when exposed to BF3.OEt2, showing that the most appropriate reagents can be selected by MN interpretation

Methylaluminoxane (MAO)-Assisted Direct Amidation of Esters

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Fast & easy preparation of 3D scaffolds from methyl benzoate by a diversity oriented synthesis strategy based on Diels–Alder and ene-reactions

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MetGem Software for the Generation of Molecular Networks Based on the t-SNE Algorithm

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Isolation of phenanthrenes and identification of phorbol ester derivatives as potential anti-CHIKV agents using FBMN and NAP from Sagotia racemosa

In an effort to identify inhibitors of Chikungunya virus (CHIKV) replication, a systematic study of 594 extracts of plant species originating from the French Guiana plateau region was performed in a virus-cell-based assay for CHIKV assay. The extract obtained from the stem bark of Sagotia racemosa was selected for its potent antiviral activity. Using a classical bioassay-guided procedure, three undescribed degraded diterpenoids, i.e. trigohowilols C and D and trigoflavidol D, as well as trigoxyphin K, stictic acid, hyperhomosekikaic acid and five known flavonoids were isolated. The structures of these compounds were elucidated by extensive NMR spectroscopic data analysis. Although trigohowilols C and D were isolated from the most active fraction they didn't show any antiviral activity. By using the Feature-Based Molecular Networking (FBMN) and Network Annotation Propagation (NAP) workflows, it has been shown that the strong anti-CHIKV activity found for this fraction might be due to the presence of analogues of 12-O-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication identified to date.status: publishe