16 research outputs found
SynthĂšse d'alcynylcarbinols fonctionnels et Ă©valuation d'analogues en tant que pharmacophores
Parmi les mĂ©tabolites secondaires extraits d'Ă©ponges marines, les produits prĂ©sentant dans leur structure un fragment alcool propargylique C3-substituĂ© chiral occupent une place particuliĂšre. Ils possĂšdent en effet des activitĂ©s biologiques trĂšs variĂ©es, notamment antibiotiques, antivirales, ou plus gĂ©nĂ©ralement cytotoxiques. Dans ces composĂ©s, le motif alcool propargylique dĂ©signĂ© ici sous le terme " alcynylcarbinol " (englobant plus explicitement les versions Ă centre carbinol substituĂ© chiral), est la caractĂ©ristique principale de ces composĂ©s pouvant vraisemblablement jouer le rĂŽle d'unitĂ© pharmacophore. Aucune Ă©tude systĂ©matique permettant de dĂ©terminer des relations structure-activitĂ© dans cette sĂ©rie de molĂ©cules n'avait cependant Ă©tĂ© entreprise jusqu'Ă rĂ©cemment. Dans le but d'identifier un fragment pharmacophore minimal et de dĂ©gager des relations structure-activitĂ©, une variation structurale systĂ©matique a donc Ă©tĂ© envisagĂ©e dans le cadre de ce travail Ă partir du squelette archĂ©typique d'un produit naturel isolĂ© de l'Ă©ponge Cribrochalina Vasculum. Le premier chapitre est un rĂ©sumĂ© bibliographique dĂ©crivant la synthĂšse et l'activitĂ© biologique de molĂ©cules prĂ©sentant un fragment alcool propargylique dans leur structure. Le second chapitre dĂ©crit une Ă©tude de relation structure-activitĂ© dans cette famille de composĂ©s Ă partir de la molĂ©cule de rĂ©fĂ©rence ((E)-icos-4-en-1-in-3-ol). La variation de quatre paramĂštres a Ă©tĂ© Ă©tudiĂ©e : la nature de chacune des deux insaturations, le configuration du centre asymĂ©trique, et le longueur de la chaĂźne lipidique saturĂ©e. Le troisiĂšme chapitre porte sur l'Ă©tude complĂšte de la synthĂšse de lipides Ă deux tĂȘtes pharmacophores de symĂ©trie C2 et sur la caractĂ©risation de composition stĂ©rĂ©ochimique des produits obtenus. Le quatriĂšme chapitre est consacrĂ© Ă la description de la synthĂšse de produits dans lesquels une unitĂ© C2 acĂ©tylĂ©nique est remplacĂ©e par un fragment C4 butadiyne ou C3 allĂšne. Le cinquiĂšme chapitre dĂ©crit la synthĂšse de lipides Ă pharmacophore dialkynylcarbinol portant des fluorophores pour l'imagerie cellulaire et les premiers tests de marquage cellulaire. Dans le sixiĂšme chapitre sont combinĂ©s les resultats des mesures d'activitĂ© cytotoxique des diffĂ©rentes sĂ©ries de molĂ©cules synthĂ©tisĂ©es. Les composĂ©s synthĂ©tisĂ©s ont Ă©tĂ© soumis Ă des mesures de cytotoxicitĂ© vis-Ă -vis de la lignĂ©e cellulaire HCT116 et la plupart ont montrĂ© des niveaux d'activitĂ© biologique remarquables. Le septiĂšme et dernier chapitre rĂ©unit les mĂ©thodes de synthĂšse et les characterisations de tous les produits obtenus lors de ce travail.Among naturally occurring secondary metabolites isolated from marine sponges the compounds with chiral propargyl alcohol unite occupy a special place. They have been shown to display the different types of biological activities, for example: antibiotic, antiviral, and more generally cytotoxic. In these compounds, the propargyl alcohol unit hereinafter as the "alkynylcarbinol" (including substituted chiral carbinol center), is the key characteristic that can have a pharmacophore fragment function. Nevertheless, no systematic study to determine structure-activity relationships in this series of molecules had been carried until recently. In order to identify a minimum pharmacophore unit and identify structure-activity relationships, systematic structural variation was therefore considered as part of this work from the archetypal structure of a natural product isolated from the sponge Cribrochalina vasculum. The first chapter is a bibliographic summary describing the synthesis and biological activity of molecules with a propargyl alcohol moiety in their structure. The second chapter describes a study of structure-activity relationship in a series of compounds from the reference molecule ((E) -icos-4-en-1-in-3-ol). The four parameter variation was studied: the nature of each of the two unsaturations, the configuration of the asymmetric center, and the length of the saturated lipid chain. The third chapter focuses on the complete study of the synthesis of lipids in two symmetrical pharmacophore heads C2 and stereochemical composition characteristics of the obtained products. The fourth chapter is devoted to the description of the synthetic products in which an acetylene C2 unit is replaced by a C4 butadiyne fragment or C3 one of allene. The fifth chapter describes the synthesis of pharmacophore dialkynylcarbinol lipids with fluorophore fragment for cell imaging and the first cell imaging tests. In the sixth chapter has combined the results of measurements of cytotoxic activity of different types of synthesized molecules. The obtained compounds were subjected to measurements of cytotoxicity against the cell line HCT116 and most of them have shown remarkable levels of biological activity. The seventh and final chapter brings together the methods of synthesis and characterizations of all products obtained during this work
On terminal alkynylcarbinols and derivatization thereof
The chemistry of three prototypes of secondary alkynylcarbinols (ACs), recently highlighted as challenging targets in anti-tumoral medicinal chemistry, is further documented by results on n-alkyl, alkynyl and alkenyl representatives. The N-naphthyl carbamate of an n-butyl-AC is thus characterized by X-ray crystallography. A novel dialkynylcarbinol (DAC) with synthetic potential is described, namely the highly dissymmetrical triisopropylsilyl-protected version of diethynylmethanol. The latter is shown to act as a dipolarophile in a selective Huisgen reaction with benzyl azide under CuAAC click conditions, giving an alkenyl-AC, where the alkene unsaturation is embedded in a 1,4-disubstituted 1,2,3-triazole ring, as confirmed by X-ray crystallography.Supplementary information (CIF file
Ethynylogation approach in antitumor lipid pharmacochemistry: from dialkynyl-carbinols to trialkynyl-carbinols
A recently proposed "ethynylogation" pharmacochemical approach, first envisaged in the series of anticancer lipidic dialkynylcarbinols (DACs) HâCâĄCâCH(OH)âCâĄCâR at the levels of the HâCâź and âźCâR bonds for R = n-C12H25, is completed here at the level of the (HO)CâH bond. The so-devised mono-lipidic trialkynylcarbinol (TAC) target (HCâĄC)2C(OH)âCâĄCR and its bis-lipidic counterpart HCâĄCâC(OH)(CâĄCR)2 were synthesized in 4 steps and with 33 % and 23 % overall yield, respectively. Their antitumor cytotoxicity has been evaluated towards HCT116 cells: while the latter TAC is totally inactive, the former DAC-ethynylogous TAC still exhibits a significant toxicity with an IC50 of 10 ”M
Functional alkynylcarbinols synthesis and their analogous evaluation as pharmacophores
Parmi les mĂ©tabolites secondaires extraits d'Ă©ponges marines, les produits prĂ©sentant dans leur structure un fragment alcool propargylique C3-substituĂ© chiral occupent une place particuliĂšre. Ils possĂšdent en effet des activitĂ©s biologiques trĂšs variĂ©es, notamment antibiotiques, antivirales, ou plus gĂ©nĂ©ralement cytotoxiques. Dans ces composĂ©s, le motif alcool propargylique dĂ©signĂ© ici sous le terme " alcynylcarbinol " (englobant plus explicitement les versions Ă centre carbinol substituĂ© chiral), est la caractĂ©ristique principale de ces composĂ©s pouvant vraisemblablement jouer le rĂŽle d'unitĂ© pharmacophore. Aucune Ă©tude systĂ©matique permettant de dĂ©terminer des relations structure-activitĂ© dans cette sĂ©rie de molĂ©cules n'avait cependant Ă©tĂ© entreprise jusqu'Ă rĂ©cemment. Dans le but d'identifier un fragment pharmacophore minimal et de dĂ©gager des relations structure-activitĂ©, une variation structurale systĂ©matique a donc Ă©tĂ© envisagĂ©e dans le cadre de ce travail Ă partir du squelette archĂ©typique d'un produit naturel isolĂ© de l'Ă©ponge Cribrochalina Vasculum. Le premier chapitre est un rĂ©sumĂ© bibliographique dĂ©crivant la synthĂšse et l'activitĂ© biologique de molĂ©cules prĂ©sentant un fragment alcool propargylique dans leur structure. Le second chapitre dĂ©crit une Ă©tude de relation structure-activitĂ© dans cette famille de composĂ©s Ă partir de la molĂ©cule de rĂ©fĂ©rence ((E)-icos-4-en-1-in-3-ol). La variation de quatre paramĂštres a Ă©tĂ© Ă©tudiĂ©e : la nature de chacune des deux insaturations, le configuration du centre asymĂ©trique, et le longueur de la chaĂźne lipidique saturĂ©e. Le troisiĂšme chapitre porte sur l'Ă©tude complĂšte de la synthĂšse de lipides Ă deux tĂȘtes pharmacophores de symĂ©trie C2 et sur la caractĂ©risation de composition stĂ©rĂ©ochimique des produits obtenus. Le quatriĂšme chapitre est consacrĂ© Ă la description de la synthĂšse de produits dans lesquels une unitĂ© C2 acĂ©tylĂ©nique est remplacĂ©e par un fragment C4 butadiyne ou C3 allĂšne. Le cinquiĂšme chapitre dĂ©crit la synthĂšse de lipides Ă pharmacophore dialkynylcarbinol portant des fluorophores pour l'imagerie cellulaire et les premiers tests de marquage cellulaire. Dans le sixiĂšme chapitre sont combinĂ©s les resultats des mesures d'activitĂ© cytotoxique des diffĂ©rentes sĂ©ries de molĂ©cules synthĂ©tisĂ©es. Les composĂ©s synthĂ©tisĂ©s ont Ă©tĂ© soumis Ă des mesures de cytotoxicitĂ© vis-Ă -vis de la lignĂ©e cellulaire HCT116 et la plupart ont montrĂ© des niveaux d'activitĂ© biologique remarquables. Le septiĂšme et dernier chapitre rĂ©unit les mĂ©thodes de synthĂšse et les characterisations de tous les produits obtenus lors de ce travail.Among naturally occurring secondary metabolites isolated from marine sponges the compounds with chiral propargyl alcohol unite occupy a special place. They have been shown to display the different types of biological activities, for example: antibiotic, antiviral, and more generally cytotoxic. In these compounds, the propargyl alcohol unit hereinafter as the "alkynylcarbinol" (including substituted chiral carbinol center), is the key characteristic that can have a pharmacophore fragment function. Nevertheless, no systematic study to determine structure-activity relationships in this series of molecules had been carried until recently. In order to identify a minimum pharmacophore unit and identify structure-activity relationships, systematic structural variation was therefore considered as part of this work from the archetypal structure of a natural product isolated from the sponge Cribrochalina vasculum. The first chapter is a bibliographic summary describing the synthesis and biological activity of molecules with a propargyl alcohol moiety in their structure. The second chapter describes a study of structure-activity relationship in a series of compounds from the reference molecule ((E) -icos-4-en-1-in-3-ol). The four parameter variation was studied: the nature of each of the two unsaturations, the configuration of the asymmetric center, and the length of the saturated lipid chain. The third chapter focuses on the complete study of the synthesis of lipids in two symmetrical pharmacophore heads C2 and stereochemical composition characteristics of the obtained products. The fourth chapter is devoted to the description of the synthetic products in which an acetylene C2 unit is replaced by a C4 butadiyne fragment or C3 one of allene. The fifth chapter describes the synthesis of pharmacophore dialkynylcarbinol lipids with fluorophore fragment for cell imaging and the first cell imaging tests. In the sixth chapter has combined the results of measurements of cytotoxic activity of different types of synthesized molecules. The obtained compounds were subjected to measurements of cytotoxicity against the cell line HCT116 and most of them have shown remarkable levels of biological activity. The seventh and final chapter brings together the methods of synthesis and characterizations of all products obtained during this work
From natural to artificial antitumor lipidic alkynylcarbinols: Asymmetric synthesis, enzymatic resolution, and refined SARs
International audienceAmong acetylenic natural products, chiral lipidic alkynylcarbinol (LAC) metabolites, mostly extracted from marine sponges, have revealed a broad spectrum of biological activities, in particular, remarkable antitumor cytotoxicity. With reference to one of the simplest natural representatives, [(S)-eicos-(4E)-en-1-yn-3-ol], and a given cancer cell line (HCT116), combined extensive efforts in chemical synthesis (relying on the use of a large chemical toolbox) and biological analysis (in vitro tests), have provided systematic structureâactivity relationships (SARs) where the initially selected four structural parameters appear as independent principal components: (i) and (ii) the sp/sp2 content and extent of the terminal and internal unsaturations adjacent to the carbinol center, (iii) the absolute configuration of the latter, (iv) the length of the n-aliphatic backbone. Two key criteria have also been established regarding the functional alkynylcarbinol pharmacophore: the alkynylcarbinol unit must be both secondary and terminal (i.e., substituted by a short ethynyl or ethenyl C2 group). This review is intended to provide a further illustration of the value of a simple rational approach for drug design, and to act as a benchmark for future optimization of LACs as antitumor agents
Synthesis of a series of tetraminic acid sulfone analogs
International audienceWe have introduced a strategy for the construction of spirocycloalkane 1 lambda(6)-isothiazolidine-1,1,4-triones through the mesylation of 1-aminocyclopentane-, 1-aminocyclohexane-, and 1-aminocycloheptanecarboxylic acid esters with methanesulfonylchloride followed by alkylation with methyl iodide and consequent cyclization in the presence of potassium tert-butoxide in N,N-dimethylformamide. The spirocycloalkane 4-amino-2,3-dihydro-1H-1 lambda(6)-isothiazole-1,1-diones were prepared via mesylation of N-methylated 1-aminocyclopentyl-, 1-aminocyclohexyl-, and 1-aminocycloheptyl carbonitriles followed by treatment of obtained N-(1-cyanocycloalkyl)-N-methylmethanesulfonamides with potassium tert-butoxide in N,N-dimethylformamide. The spiro 4-amino-2,3-dihydro-1H-1 lambda(6)-isothiazole-1,1-diones were converted into the target spiro 1 lambda(6)-isothiazolidine-1,1,4-triones by acid-catalyzed hydrolysis. The structure of a target spiro compound and its isolated key intermediate was confirmed by X-ray diffraction study. The interaction of spiro 1 lambda(6)-isothiazolidine-1,1,4-triones with N,N-dimethylformamide dimethyl acetal leads to the formation of spiro 5-[(Z)-(dimethylamino)methylidene]-1 lambda(6)-isothiazolidine-1,1,4-triones
Linear and nonlinear optical properties of a quadrupolar carbo-benzene and its benzenic parent: The carbo-merization effect
International audienceHerein, the optical properties of thiophene-functionalized quadrupolar carbo-benzenes and a benzenic parent, of generic structure ThâCtriple bondCâ[core]âCtriple bondCâTh, Th = R2C4HS, are comparatively investigated. Beyond the previously unknown dioctylthienylethynylbenzene (core = p-C6H4, R = nOct), two bis-dialkylthienylethynyl-carbo-benzenes (core = C18Ph4, R = nOct, nBu) are envisaged for the unique "carbo-aromatic" character of the C18 macrocycle. The three targets were synthesized from the corresponding ethynylthiophenes in 47, 20 and 10% yield, respectively, then characterized by classical methods such as NMR spectroscopy, and X-ray crystallography for one of the carbo-benzenes. Regarding linear and nonlinear optical properties, our results show that the carbo-merization induces a significant shift to lower energies of the one-photon electronic excitations accompanied by an 8-fold increase of the molar extinction coefficient compared to the parent molecule. Intriguingly, these excitations lead to a broad band of photoluminescence comprising decay transitions of the type S1 â S0 but also of the type S2 â S0. This phenomenon of emission from higher excited states, which is contrary to Kasha's rule, is assigned to - or revealed by - a reduction of the internal conversion efficiency between S2 and S1. Two-photon induced transitions are also enhanced, the two-photon absorption cross-section (Ï2PA) being in average five times larger for the carbo-benzenes than for their benzene parent in the wavelength range 650â950 nm, with a maximum of Ï2PA = 1430 GM (1 GM = 10â50 cm4 s/photon). Beyond a moderate nonlinearity, this comparative study provides quantitative insights about the way carbo-merization or insertion of a Ï-conjugated macrocycle between chromophoric functions (here thiophene rings) can tune optical properties of organic molecules. The optical properties of the bis-dialkylthienylethynyl-carbo-benzenes are also discussed in regard of recent reports on organic chromophores based on other types of Ï-conjugated macrocyclic cores
Linear and nonlinear optical properties of a quadrupolar carbo-benzene and its benzenic parent: The carbo-merization effect
International audienceHerein, the optical properties of thiophene-functionalized quadrupolar carbo-benzenes and a benzenic parent, of generic structure ThâCtriple bondCâ[core]âCtriple bondCâTh, Th = R2C4HS, are comparatively investigated. Beyond the previously unknown dioctylthienylethynylbenzene (core = p-C6H4, R = nOct), two bis-dialkylthienylethynyl-carbo-benzenes (core = C18Ph4, R = nOct, nBu) are envisaged for the unique "carbo-aromatic" character of the C18 macrocycle. The three targets were synthesized from the corresponding ethynylthiophenes in 47, 20 and 10% yield, respectively, then characterized by classical methods such as NMR spectroscopy, and X-ray crystallography for one of the carbo-benzenes. Regarding linear and nonlinear optical properties, our results show that the carbo-merization induces a significant shift to lower energies of the one-photon electronic excitations accompanied by an 8-fold increase of the molar extinction coefficient compared to the parent molecule. Intriguingly, these excitations lead to a broad band of photoluminescence comprising decay transitions of the type S1 â S0 but also of the type S2 â S0. This phenomenon of emission from higher excited states, which is contrary to Kasha's rule, is assigned to - or revealed by - a reduction of the internal conversion efficiency between S2 and S1. Two-photon induced transitions are also enhanced, the two-photon absorption cross-section (Ï2PA) being in average five times larger for the carbo-benzenes than for their benzene parent in the wavelength range 650â950 nm, with a maximum of Ï2PA = 1430 GM (1 GM = 10â50 cm4 s/photon). Beyond a moderate nonlinearity, this comparative study provides quantitative insights about the way carbo-merization or insertion of a Ï-conjugated macrocycle between chromophoric functions (here thiophene rings) can tune optical properties of organic molecules. The optical properties of the bis-dialkylthienylethynyl-carbo-benzenes are also discussed in regard of recent reports on organic chromophores based on other types of Ï-conjugated macrocyclic cores
Asymmetric Synthesis and Biological Evaluation of Natural or Bioinspired Cytotoxic <i>C</i><sub>2</sub>âSymmetrical Lipids with Two Terminal Chiral Alkynylcarbinol Pharmacophores
Bidirectional
syntheses of <i>C</i><sub>2</sub>-symmetrical
lipids embedding two terminal alkynylcarbinol pharmacophores are reported.
Naturally occurring chiral alkenylalkynylcarbinol units were generated
using Puâs procedure for enantioselective addition of terminal
alkynes to aldehydes, allowing the first asymmetric synthesis of (3<i>R</i>,4<i>E</i>,16<i>E</i>,18<i>R</i>)-icosa-4,16-diene-1,19-diyne-3,18-diol, isolated from <i>Callyspongia
pseudoreticulata</i>. Two synthetic analogues embedding the recently
uncovered (<i>S</i>)-dialkynylcarbinol pharmacophore were
secured using Carreiraâs procedure adapted to ynal substrates.
The dramatic effect of the carbinol configuration on cytotoxicity
was confirmed with submicromolar IC<sub>50</sub> values against HCT116
cells