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ABSTRACT: A new derivative of the strained 3,3,6,6-tetramethylthiacycloheptyne (TMTH) bearing a functional handle is reported. Following an optimized synthesis, the handle was introduced by mild alkylation of the sulphur atom. The resulting functionalized strained 4,5-didehydro-3,3,6,6-tetramethyl-2,3,6,7-tetrahydrothiepinium (TMTI) proved to be stable and underwent extremely fast [3+2] cycloaddition reaction with benzyl azide in both organic and aqueous solvents. The reaction was equally efficient in cell lysate and serum and therefore opens interesting prospects for chemical-biology applications.
Chemical Communications 08/2012; 48(74):9308-9. · 6.17 Impact Factor
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Florence Lebon,
Cécile Pégurier,
Marie Ledecq,
Benoit Mathieu,
Nathalie Bosman,
Anne Frycia,
Sébastien Lengelé,
Kashinath Dhurke,
Ananda Kumar Kanduluru,
Stéphane Meunier, Alain Wagner,
Christian Wolff,
Laurent Provins
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ABSTRACT: A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.
Bioorganic & medicinal chemistry letters 04/2012; 22(12):3978-82. · 2.65 Impact Factor
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Fanny Varenne,
Mélanie Bourdillon,
Michel Meyer,
Yi Lin,
Marie Brellier,
Rachid Baati,
Loïc J Charbonnière, Alain Wagner,
Eric Doris,
Frédéric Taran,
Agnès Hagège
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ABSTRACT: A screening strategy based on hyphenated capillary electrophoresis and inductively coupled plasma mass spectrometry (CE-ICP-MS) was developed to classify phosphorylated ligands according to their europium(III) binding affinity in a hydro-organic medium (sodium formate, pH 3.7, H(2)O/MeOH 90:10, v/v). Taking advantage of the high sensibility of ICP-MS for detecting phosphorus, this method enabled to assess the affinity of a variety of phosphorylated compounds, including phosphine oxides, thiophosphines, phosphonates, and phosphinates, in less than 1h and using less than 5 ng of substance. By varying the total europium concentration, complexation constants could be determined according to a sequential multiple run strategy, which proved to be in excellent agreement with the values obtained by UV-Vis absorption spectrophotometric titrations.
Journal of chromatography. A 03/2012; 1229:280-7. · 4.19 Impact Factor
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ABSTRACT: A new concept of a chemically deactivatable quencher is proposed for a FRET-based probe that turns-on its fluorescence by either an enzymatic cleavage or a chemical reagent (sodium dithionite). This concept allowed us to quantify the caspase-3 cleavage activity in solution and to reveal unreacted probes in cell experiments.
Chemical Communications 02/2012; 48(26):3224-6. · 6.17 Impact Factor
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ABSTRACT: Antioxidative activity expressed as protection of thymidine has been investigated for a set of 30 pulvinic acid derivatives. A combination of in vitro testing and in silico modeling was used for synthesis of new potential antioxidants. Experimental data obtained from a primary screening test based on oxidation under Fenton conditions and by an UV exposure followed by back-titration of the amount of thymidine remaining intact have been used to develop a computer model for prediction of antioxidant activity. Structural descriptors of 30 compounds tested for their thymidine protection activity were calculated in order to define the structure-property relationship and to construct predictive models. Due to the potential nonlinearity, the counter-propagation artificial neural networks were assessed for modeling of the antioxidant activity of these compounds. The optimized model was challenged with 80 new molecules not present in the initial training set. The compounds with the highest predicted antioxidant activity were considered for synthesis. Among the predicted structures, some coumarine derivatives appeared to be especially interesting. One of them was synthesized and tested on in vitro assays and showed some antioxidant and radioprotective activities, which turned out as a promising lead toward more potent antioxidants.
Journal of Chemical Information and Modeling 11/2011; 51(12):3050-9. · 4.68 Impact Factor
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ABSTRACT: We describe a general user-friendly platform for fine-tuning the drug release properties of low-molecular-weight hydrogels by a combination of supramolecular co-assembly of complementary molecular structures and controlled photochemical thiol–ene cross-linking. Other critical features such as thermomechanical stability and morphology of the nanostructured hydrogels are also tailored by this approach.
Journal of Materials Chemistry 11/2011; · 5.97 Impact Factor
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ABSTRACT: Cationic surfactants easily interact with plasmid DNA to form small lipoplexes. However, their detergent behavior and associated biological toxicity limit their use as gene delivery vectors. We have incorporated a diacetylene motif in the hydrophobic chain of cationic surfactants. By using UV irradiation, the small cationic micelles (9 nm) obtained with diacetylenic detergents were photopolymerized into 40 nm spheres. Electrostatic interactions with plasmid DNA led to the formation of 45 nm lipoplexes at N/P = 5 ratio. In vitro transfection of the pCMV-Luciferase plasmid resulted in gene expression (>10(10) RLU/mg protein) at the same ratio, comparable with the commercially available JetSi-ENDO gene delivery system. This new and versatile class of molecules could lead to a new generation of in vivo gene delivery vectors.
Bioconjugate Chemistry 09/2011; 22(10):1916-23. · 4.93 Impact Factor
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ABSTRACT: We synthesized new amphiphiles comprised of a single diacetylenic chain and an oligoethylenoxide polar chain linked by an amide bond. In aqueous medium, they are not soluble at room temperature but form weak gels. Electron microscopy studies have shown that they self-assemble into helical tapes or nanotubes with lengths of several micrometers, and inner and outer diameters of 50 ± 1 and 59 ± 1 nm, respectively. The wall has a thickness of 10 ± 1 nm for both kinds of objects and has an amphiphile bilayer structure. The hydrophobic chains are ordered, and the amide groups are linked with each other by H-bonds. The dissociation of the tubes is a first-order transition with an enthalpy of ca. 40 kJ mol(-1). The nanotubes were photopolymerized to yield purple solutions consisting of helical tapes and almost flat ribbons. The polymers exhibit irreversible thermochromism upon heating.
Langmuir 09/2011; 27(19):12149-55. · 4.19 Impact Factor
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ABSTRACT: Interest in cleavable linkers is growing due to the rapid development and expansion of chemical biology. The chemical constrains imposed by the biological conditions cause significant challenges for organic chemists. In this review we will present an overview of the cleavable linkers used in chemical biology classified according to their cleavage conditions by enzymes, nucleophilic/basic reagents, reducing agents, photo-irradiation, electrophilic/acidic reagents, organometallic and metal reagents, oxidizing reagents.
Bioorganic & medicinal chemistry 07/2011; 20(2):571-82. · 2.82 Impact Factor
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ABSTRACT: An unprecedented and highly diastereoselective 6-endo-trig cyclization of 2-alkenyl-1,3-dithiolanes has been developed yielding trans-decalins, an important scaffold present in numerous di- and triterpenes. The novelty of this 6-endo-trig cyclization stands in the stepwise mechanism involving 2-alkenyl-1,3-dithiolane, acting as a novel latent initiator. It is suggested that the thioketal opens temporarily under the influence of TMSOTf, triggering the cationic 6-endo-trig cyclization, and closes after C-C bond formation and diastereoselective protonation to terminate the process. DFT calculations confirm this mechanistic proposal and provide a rationale for the observed diastereoselectivity. The reaction tolerates a wide range of functionalities and nucleophilic partners within the substrate. We have also shown that the one-pot 6-endo-trig cyclization followed by in situ 1,3-dithiolane deprotection afford directly the corresponding ketone. This improvement allowed the achievement of the shortest total synthesis of triptophenolide and the shortest formal synthesis of triptolide.
The Journal of Organic Chemistry 03/2011; 76(9):3274-85. · 4.45 Impact Factor
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ABSTRACT: Nerve agents are highly toxic organophosphorus compounds with strong inhibition potency against acetylcholinesterase (AChE). Herein, we describe two first extremely promising uncharged reactivators for poisoned human AChE with a superior or similar in vitro ability to reactivate the enzyme as compared to that of HI-6, obidoxime, TMB-4 and HLö-7.
Chemical Communications 03/2011; 47(18):5295-7. · 6.17 Impact Factor
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the journal of physical chemistry. 01/2011; 115:7319.
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Macromolecular Chemistry and Physics 01/2011; 212:111. · 2.36 Impact Factor
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ABSTRACT: A high-throughput screening method has highlighted the marked antioxidant activity of some pulvinic acid derivatives (PADs) towards oxidation of thymidine, under γ and UV irradiation, and Fenton-like conditions. Here, we report the synthesis of a series of new hydrophilic PADs and the evaluation of their radioprotective efficacy in cell culture. Using a cell-based fluorescent assay, we show that some of these compounds have a pronounced ability to prevent cell death caused by radiation and to allow the subsequent resumption of proliferation. Thus, PADs may be considered as a novel class of radioprotective agents.
ChemMedChem 01/2011; 6(3):561-9. · 3.15 Impact Factor
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Macromolecular Chemistry and Physics 11/2010; 212(2):111 - 117. · 2.36 Impact Factor
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ChemBioChem 11/2010; 11(17):2359-61. · 3.94 Impact Factor
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ABSTRACT: N-Methyl-N-(pentacosa-10,12-diyn)-propargylamine organizes itself into an unusual supramolecular pH- and thermo-responsive system. Studies have showed that submillimetric length hollow laths form this unique structure in the presence of hydrochloric acid. Specific chemical modifications on the initial molecule and small-angle neutron scattering experiments were performed to understand the structure of this system. Our results allow us to suggest a possible structure of the laths.
The Journal of Physical Chemistry B 10/2010; 114(39):12495-500. · 3.70 Impact Factor
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ChemMedChem 10/2010; 5(12):1983-8. · 3.15 Impact Factor
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Brice Nadal,
Sophie A-L Thetiot-Laurent,
Serge Pin,
Jean-Philippe Renault,
Damien Cressier,
Ghassoub Rima,
Antoine Le Roux,
Stéphane Meunier, Alain Wagner,
Claude Lion,
Thierry Le Gall
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ABSTRACT: The synthesis of three types of pulvinic acid analogues, using a diversity-oriented strategy starting from a single compound, dimethyl l-tartrate, is described. Lacey-Dieckmann condensation, alcohol dehydration and Suzuki-Miyaura cross-couplings were employed in the course of the analogues syntheses. The evaluation of the antioxidant properties of the 28 synthesized analogues was carried out using antioxidant capacity assays (protection of thymidine and β-carotene) and free radical scavenging assays (DPPH radical and ABTS radical cation). This allowed to assess the relative influence of the groups bonded to the tetronic ring and to the exocyclic double bond on the activity, as well as the importance of this exocyclic double bond. It was shown that the presence of an electron-donating group on the 3-position of the tetronic ring had a beneficial effect. It was shown in several assays that the presence of the exocyclic bond was not crucial to the activity.
Bioorganic & medicinal chemistry 09/2010; 18(22):7931-9. · 2.82 Impact Factor
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ABSTRACT: A concise and diastereoselective formal total synthesis of triptolide, a natural product with a wide range of biological properties, is described. The key reaction is an unprecedented 6-endo-Trig cationic cyclization of a 2-alkenyl-1,3-dithiolane precursor induced by TMSOTf as Lewis acid.
Chemical Communications 08/2010; 46(31):5778-80. · 6.17 Impact Factor
