Synthèse et étude des propriétés hôte-invité de récepteurs hétéroditopiques de type calix[6]crypt-(thio)urée

La chimie supramoléculaire est un domaine qui porte sur l’étude des interactionsfaibles entre molécules. Ces interactions sont très répandues dans les systèmes naturels et denombreux récepteurs moléculaires synthétiques ont été développés, soit pour un apportthéorique à la compréhension de ces processus de reconnaissance, soit pour d’éventuellesapplications en biologie ou en chimie analytique par exemple.Les calix[6]arènes sont des composés intéressants pour la reconnaissance moléculaire.Ils possèdent une cavité idéale pour l’inclusion de petites molécules et peuvent être modifiéspar l’ajout de divers motifs de reconnaissance. Le premier calix[6]crypturée préalablementétudié au sein du Laboratoire de Chimie Organique est un récepteur dont la cavité aromatiqueest juxtaposée à un motif de reconnaissance pour anions. Ce dernier est composé d’unchapeau à base de tren (tris(2-aminoéthyl)amine) portant trois groupes urée. Ce récepteurpossède notamment une forte sélectivité pour le chlorure et une forte affinité pour les pairesd’ions organiques de type chlorure d’ammonium, dans un solvant apolaire (CDCl3).Cependant, ces propriétés de reconnaissance sont beaucoup plus limitées dans un solvantprotique (CD3OD), ce qui restreint les éventuelles applications. L’objectif de ces travaux a étéde synthétiser de nouveaux dérivés avec une modification autour du site tris-urée pourrenforcer les propriétés de reconnaissance, notamment en milieu protique.La première stratégie a consisté à agrandir le chapeau cryptant reliant les trois groupesurée. Trois modes différents de complexation d’ammonium intra-cavitaire ont été mis enévidence dans un solvant apolaire, dont deux sont remarquables. Avec un anion peucoordinant (le picrate), le récepteur protoné inclut l’ammonium selon un processusallostérique pour donner un complexe dicationique. Avec la protonation du récepteur et unanion dichargé (SO42-), l’inclusion de l’ammonium constitue un complexe cascade, stable enmilieu protique.La deuxième stratégie a consisté à supprimer les groupes méthyle du petit colcalixarénique via une réaction de déméthylation sélective pour obtenir le calix[6]crypturée1,3,5-trishydroxyle. Dans un solvant apolaire, ce récepteur a montré une plus forte sélectivitépour la complexation de paires d’ions par rapport à la complexation d’anions, permettant parexemple de complexer le chlorhydrate de O,O-diméthyldopamine.La troisième stratégie a été de synthétiser le calix[6]cryptothiourée, un récepteur dontle chapeau comporte trois groupes thiourée. Cette modification structurale a fortementrenforcé la complexation d’anions mais n’a pas favorisé la complexation de paires d’ions dansun solvant protique.Enfin, la complexation de zwittérions a été testée sur l’ensemble de ces récepteurs et lecalix[6]cryptothiourée s’est avéré être un remarquable complexant de la B-alanine bétaïne.Dans un mélange protique (CD3OD/CDCl3 1:1) la constante d’association est élevée (K ≈ 104M-1) et supérieure d’au moins trois ordres de grandeur par rapport aux autres zwittérionstestés. C’est à notre connaissance un des rares récepteurs de bétaïnes et le premier à êtresélectif pour la B-alanine bétaïne. Enfin, le biomimétisme du mode de reconnaissance a étémontré par comparaison avec une protéine transporteur de bétaïne (Corynebacteriumglutamicum).Doctorat en sciences, Spécialisation chimieinfo:eu-repo/semantics/nonPublishe

Acid-base modulation of a versatile heteroditopic calix[6]arene based receptor

A new calix[6]crypturea (3) has been efficiently synthesized through a domino Staudinger/aza-Wittig reaction followed by a [1 + 1] macrocyclization step. In comparison to the previously reported tren-based calix[6]crypturea, this heteroditopic receptor 3 displays a more flexible and larger tris-ureido cap. Due to this structural alteration, 3 exhibits unique host-guest properties: (i) the protonation of its basic cap leads to a rigidification of the whole structure and, thus, allosteric control of the binding properties and selective guest switching processes are possible, (ii) its versatility is unprecedented in the literature since it can bind either neutral molecules, anions, primary/secondary ammonium ions, quaternary ammonium ions or contact ion pairs according to different modes of recognition and with a remarkable selectivity within each family of guest, (iii) cascade complexes even stable in a protic environment can be obtained. These remarkable features are nicely illustrated by the fact that, according to the nature of its counterion, an ammonium ion R 1R 2NH 2 + can be accommodated into the cavity either as an independent guest, as a contact ion-pair or as a cascade complex. All these results are reminiscent of biological receptors and validate the strategy that consists of designing receptors presenting a high flexibility that can be controlled by an external stimulus. © 2011 The Royal Society of Chemistry.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A biomimetic heteroditopic receptor for zwitterions in protic media

The efficient synthesis of calix[6]cryptothiourea 6 was achieved through a two-step sequence that involves a key [1+1] macrocyclization step. It was shown by NMR spectroscopy that this heteroditopic receptor can bind zwitterions in protic media with an outstanding selectivity for balanine betaine G5, which is likely due to a high complementarity between the two partners. This result constitutes a rare example of cavity complexation of a zwitterion by a calix[6]arene. In comparison with the parent urea-based receptors, 6 behaves as a much more efficient host for betaines. This strengthening of the binding properties is due to the better preorganization of the tripodal hydrogenbonding cap as well as to the higher acidity of the thiourea groups and their poor ability to self-associate. Remarkably, host 6 is able to perform solid-liquid as well as liquid-liquid extraction of G5. Finally, 6 provides an excellent structural model for the binding site of glycine betaine G4 encountered in natural systems.SCOPUS: ar.jFLWNAinfo:eu-repo/semantics/publishe

Efficient 'one-pot' methodology for the synthesis of novel tetrahydro-β-carboline, tetrahydroisoquinoline and tetrahydrothienopyridine derivatives

A simple and efficient 'one-pot' methodology was developed to generate a new series of tetrahydro-β-carboline (THBC), tetrahydroisoquinoline (THIQ) and tetrahydrothienopyridine (THTP) derivatives. The key step of the methodology is based on a Pictet-Spengler type cyclization of a reactive N-carbamyliminium ion. This methodology was applied to the synthesis of a library of 32 compounds with potential anti-tumoral activity. © 2013 Elsevier Ltd. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Metal-free synthesis of an estetrol key intermediate under intensified continuous flow conditions

peer reviewedEstetrol is a natural biogenic estrogen with a promising future in hormonal-dependent treatments and growing established markets for oral contraception. Approved in 2021 by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in combination with drospirenone as the fifth generation of combined oral contraceptive pills, efforts toward cost-efficient and intensified large-scale synthesis are therefore required to meet a rapidly increasing demand worldwide. Herein we present a study aiming at the intensified preparation of a key enone intermediate for the preparation of estetrol. This approach relies on a unique methodology, where preliminary computational data guided the framework for experimental design and assess the feasibility under flow conditions, hence significantly reducing the amount of unguided experimental work. Chemical and chemical engineering innovations rely on the thermolysis of a key sulfoxide derivative of estrone, the elimination of which was carefully tailored for minimizing side-product formation and for improving robustness and productivity. Upon optimization, the thermolysis process was amenable to pilot production, leading to an unprecedented space–time yield of 1.13 kg L−1 h−1. With these metrics transposed to the entire production scheme toward estetrol, a forecast of several millions of doses (15 mg formulation) is therefore achievable with a minimal overall footprint

CCDC 820544: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

Synthesis and study of new biomimetic calix[6]tren based complexes

More than 30% of enzymes present a metal ion in their active site that is key forcatalysis. Interesting sub-families present a mononuclear active site where a single metal ion(Zn2+ or Cun+) is coordinated to a polyhistidine core. The elaboration of model compounds isimportant for understanding the fundamental mechanisms involved in their bio-catalyticcycles.1 We have developed calix[6]arene based ligands presenting an aza cap covalentlylinked to the calixarene moiety, which offers a metal coordination site and a well-definedhydrophobic cavity. This assembly allows and controls exogenous ligand binding to a metalcenter. One of these ligands, calix[6]tren (1), shows versatile host-guest properties oncecomplexed to Cun+ but is also a remarkable receptor for ammonium ions and polar neutralmolecules,2 as well as a trigger for host/guest interconverion3 and for dioxygen activation.4The development of efficient synthetic methodologies for the selective functionalization ofcalix[6]tren is now required in order to tune its properties by the modification of thecoordination sphere of the metal and by obtaining surface graftable analogues that can bestudied in water.For these purposes, different calixarenes were synthesized:- A “two-story” calix[6]amidotren (2) to expand the available space underneath thecap to allow simultaneous coordination of several guests and to study its catalytic properties;- A calix[6]tren-trisPhOH (3) amending the first and second coordination sphere of themetal in order to study its effects on coordination and reactivity;- A calix[6]tren decorated with an arm on the cap bearing an azide function (4) inorder to be immobilized on the surface and study its properties in water: these functionalizedsurfaces will present unique electrocatalytic and redox detection properties in aqueousmedium.Synthesis, complexation, characterization and electrochemical behavior of thedifferent compounds in solution and immobilized on surface will be presented and discussed.0info:eu-repo/semantics/nonPublishe

Incorporation of a 3-(2,2,2-trifluoroethyl)-γ-hydroxy-γ-lactam motif in the side chain of 4-aminoquinolines. Syntheses and antimalarial activities.

In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated γ-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19-50 nM with resistance indices in the range of 1.0-2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 μM. The most promising compounds (82 and 84) showed significant IC₅₀ values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Supramolecular Assistance for the Selective Demethylation of Calixarene-Based Receptors

The selective demethylation of methoxy groups of several multifunctionalized 1,3,5-trimethoxycalix[6]arene-based receptors has been achieved. It is shown in this study that the best reagent is trimethylsilyl iodide (TMSI) and that the conformation adopted by the calixarene core is crucial for both the selectivity and the efficiency of the process. A key feature appears to be the "in" or "out" orientation of the methoxy substituents relative to the macrocyclic cavity. If projected inward, the reaction is slow and not selective. If projected outward, the reaction is fast and selective. A strategy that consists of exploiting the host-guest properties of the receptors to change their conformation and to permit their selective demethylation has been developed. Four cases of such a supramolecular assistance are reported, demonstrating the efficiency of the strategy. Such an allosteric control is highly reminiscent of biological processes allowing selective transformation of multifunctional molecules. (Figure Presented).SCOPUS: ar.jinfo:eu-repo/semantics/publishe