Publications by authors named "Clotilde Ferroud"

24 Publications

  • Page 1 of 1

Targeting the aryl hydrocarbon receptor with a novel set of triarylmethanes.

Eur J Med Chem 2020 Dec 2;207:112777. Epub 2020 Sep 2.

Departament de Farmacologia, Facultat de Farmàcia, Universitat de València. Av. Vicente Andrés Estellés, S/n, 46100, Burjassot, Valencia, Spain. Electronic address:

The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroaromatic (indole, quinoline or thiophene) rings seem to be prone to AhR activation unlike phenyl substituted or benzotriazole derivatives. A molecular docking analysis with the AhR ligand binding domain (LBD) showed similarities in the binding mode and in the interactions of the most potent TAM identified 4-(pyridin-2-yl (thiophen-2-yl)methyl)phenol (22) compared to the endogenous AhR agonist 5,11-dihydroindolo[3,2-b]carbazole-12-carbaldehyde (FICZ). Finally, in silico predictions of physicochemical and biopharmaceutical properties for the most potent agonistic compounds were performed and these exhibited acceptable druglikeness and good ADME profiles. To our knowledge, this is the first study assessing the AhR modulatory effects of unsymmetrical TAM class of compounds.
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http://dx.doi.org/10.1016/j.ejmech.2020.112777DOI Listing
December 2020

Pegylated triarylmethanes: Synthesis, antimicrobial activity, anti-proliferative behavior and in silico studies.

Bioorg Chem 2020 03 22;96:103591. Epub 2020 Jan 22.

Equipe de Chimie Moléculaire du Laboratoire Génomique, Bioinformatique et Chimie Moléculaire (EA 7528), Conservatoire National des Arts et Métiers (Cnam), 2 Rue Conté, HESAM Université, 75003 Paris, France. Electronic address:

We describe herein the synthesis, characterization and biological studies of novel PEGylated triarylmethanes. Non-symmetrical and symmetrical triarylmethanes series have been synthesized by Friedel-Crafts hydroxyalkylation or directly from bisacodyl respectively followed by a functionalization with PEG fragments in order to increase bioavailability and biological effectiveness. The antimicrobial activity was investigated against Gram-positive and Gram-negative foodborne pathogens and against Candida albicans, an opportunistic pathogenic yeast. The anti-biocidal activity was also studied using Staphylococcus aureus as a reference bacterium. Almost all PEGylated molecules displayed an antifungal activity comparable with fusidic acid with MIC values ranging from 6.25 to 50 μg/mL. Compounds also revealed a promising antibiofilm activity with biofilm eradication percentages values above 80% for the best molecules (compounds 4d and 7). Compounds 7 and 8b showed a modest antiproliferative activity against human colorectal cancer cell lines HT-29. Finally, in silico molecular docking studies revealed DHFR and DNA gyrase B as potential anti-bacterial targets and in silico predictions of ADME suggested adequate drug-likeness profiles for the synthetized triarylmethanes.
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http://dx.doi.org/10.1016/j.bioorg.2020.103591DOI Listing
March 2020

Development, synthesis, and Ga-Labeling of a Lipophilic complexing agent for atherosclerosis PET imaging.

Eur J Med Chem 2019 Aug 2;176:129-134. Epub 2019 May 2.

Université de La Réunion, Inserm, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Plateforme CYROI, 2 rue Maxime Rivière, 97490, Sainte-Clotilde, Réunion, France; CHU de La Réunion, Allée des Topazes, 97400, Saint-Denis, Réunion, France. Electronic address:

Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Atherosclerosis accounts for 50% of deaths in western countries. This multifactorial pathology is characterized by the accumulation of lipids and inflammatory cells within the vascular wall, leading to plaque formation. We describe herein the synthesis of a PCTA-based Ga chelator coupled to a phospholipid biovector 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), which is the main constituent of the phospholipid moiety of High-Density Lipoprotein (HDL) phospholipid moiety. The resulting Ga-PCTA-DSPE inserted into HDL particles was compared to F-FDG as a PET agent to visualize atherosclerotic plaques. Our agent markedly accumulated within mouse atheromatous aortas and more interestingly in human endarterectomy carotid samples. These results support the potential use of Ga-PCTA-DSPE-HDL for atherosclerosis PET imaging.
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http://dx.doi.org/10.1016/j.ejmech.2019.05.002DOI Listing
August 2019

Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors.

Philos Trans R Soc Lond B Biol Sci 2018 06;373(1748)

CNRS FRE3600 ETaC, bât. IBCG, 31062 Toulouse, France

DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound and its derivative showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound binds to the PRMT4 active site, displacing strongly the -adenosyl-l-methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.
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http://dx.doi.org/10.1098/rstb.2017.0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915716PMC
June 2018

New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling.

Eur J Med Chem 2018 Feb 31;146:577-587. Epub 2018 Jan 31.

Equipe de Chimie Moléculaire du Laboratoire CMGPCE, EA 7341, Conservatoire National des Arts et métiers, 2 rue Conté, 75003, Paris, France. Electronic address:

In this work, a serie of cyclocoumarol derivatives was designed, synthesized, characterized and studied for their potentialities as selective inhibitors of COX-2. All target compounds have been screened for their anti-inflammatory activity by the assay of PGE production. Among them, compound 5d exhibited the most potent inhibitory activity with a PGE inhibition compared to NS-398 (79% and 88% respectively) and showed non-inhibitory activity towards the COX-1 enzyme. Docking studies revealed the capacity of this compound to occupy the selective COX-2 cavity establishing additional hydrogen bonds between the oxygen of the methoxy group and the His90 and Arg513 of the binding site of the enzyme.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.054DOI Listing
February 2018

Update on COX-2 Selective Inhibitors: Chemical Classification, Side Effects and their Use in Cancers and Neuronal Diseases.

Curr Top Med Chem 2017 ;17(26):2935-2956

Equipe de Chimie Moleculaire, Laboratoire de Chimie Moleculaire, Genie des Procedes Chimiques et Energetiques, EA7341, Conservatoire National des Arts et Metiers, 2 rue Conte, 75003 Paris. France.

Inflammation is a complex phenomenon necessary in human defense mechanisms but also involved in the development of some human diseases. The discovery of cyclooxygenase-2 (COX- 2) improved the pharmacology of nonsteroidal anti-inflammatory drugs (NSAID) giving a clear mechanism for prostaglandin regulation in vivo and providing a new target for the development of COX-2-selective drugs without gastrointestinal side-effects. Keeping in view the importance of this pharmacological class, several literature reports have underlined the impact of these antiinflammatory compounds in therapeutics. The present review considers the most recently published literature concerning COX-2 inhibitors until 2016. Through a wide chemical classification, the last developments concerning this therapeutic family by highlighting structure-activity relationships insights and mechanisms are presented. A summary of the principal adverse effects observed and an overview of the new potential therapeutic indications for COX-2 inhibitors are also reported.
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http://dx.doi.org/10.2174/1568026617666170821124947DOI Listing
November 2017

Fishing Anti-Inflammatories from Known Drugs: In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues.

Curr Top Med Chem 2017 Aug 17. Epub 2017 Aug 17.

Grupo de Investigación Ambiental (GIA), Fundación Universitaria Tecnológico de Comfenalco, Facultad de Ingenierías, Programa de Ingeniería de Procesos, Cartagena de Indias, Bolívar 130001. Colombia.

Herein is described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative. We describe the potential of TOMOCOMD-CARDD methods to find out new anti-inflammatory drug-like agents from a diverse series of compounds using the total and local atom based bilinear indices as molecular descriptors. The models obtained were validated by biological studies, identifying BSL as the first anti-inflammatory lead-like using in silico repurposing from commercially available drugs. Several biological in vitro and in vivo assays were performed in order to understand its mechanism of action. A set of analogues of BSL was prepared using low-cost synthetic procedures and further biologically investigated in zebrafish models. Compound 5c and 7e exhibited the best antiinflammatory activities and represent new promising anti-inflammatory agents for further preclinical development.
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http://dx.doi.org/10.2174/1568026617666170817161953DOI Listing
August 2017

Rational Design of Bisubstrate-Type Analogues as Inhibitors of DNA Methyltransferases in Cancer Cells.

J Med Chem 2017 06 23;60(11):4665-4679. Epub 2017 May 23.

ETaC, Epigenetic Targeting of Cancer, CRDPF, CNRS-Pierre Fabre USR3388 , 3 Avenue H. Curien, 31035 Toulouse cedex 01, France.

Aberrant DNA hypermethylation of promoter of tumor suppressor genes is commonly observed in cancer, and its inhibition by small molecules is promising for their reactivation. Here we designed bisubstrate analogues-based inhibitors, by mimicking each substrate, the S-adenosyl-l-methionine and the deoxycytidine, and linking them together. This approach resulted in quinazoline-quinoline derivatives as potent inhibitors of DNMT3A and DNMT1, some showing certain isoform selectivity. We highlighted the importance of (i) the nature and rigidity of the linker between the two moieties for inhibition, as (ii) the presence of the nitrogen on the quinoline group, and (iii) of a hydrophobic group on the quinazoline. The most potent inhibitors induced demethylation of CDKN2A promoter in colon carcinoma HCT116 cells and its reactivation after 7 days of treatment. Furthermore, in a leukemia cell model system, we found a correlation between demethylation of the promoter induced by the treatment, chromatin opening at the promoter, and the reactivation of a reporter gene.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00176DOI Listing
June 2017

An efficient and selective microwave-assisted Claisen-Schmidt reaction for the synthesis of functionalized benzalacetones.

Springerplus 2015 14;4:221. Epub 2015 May 14.

Laboratoire Chimie Moléculaire, génie des procédés chimiques et énergétiques (CMGPCE), EA 7341- Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.

A simple and direct method for the Claisen-Schmidt reaction to prepare functionalized α,β-unsaturated ketones has been developed. Microwave irradiation of aldehydes with acetone produces benzalacetones selectively without self-condensation product in very short reaction times and good yields. Graphical AbstractGraphics for use in the Table of Contents.
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http://dx.doi.org/10.1186/s40064-015-0985-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456587PMC
June 2015

Development and validation of an efficient ultrasound assisted extraction of phenolic compounds from flax (Linum usitatissimum L.) seeds.

Ultrason Sonochem 2015 Sep 28;26:176-185. Epub 2015 Feb 28.

Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC), UPRES EA 1207, Université d'Orléans, Chartres, France. Electronic address:

Flaxseed accumulates in its seedcoat a macromolecular complex composed of lignan (secoisolariciresinol diglucoside, SDG), flavonol (herbacetin diglucoside, HDG) and hydroxycinnamic acids (p-couramic, caffeic and ferulic acid glucosides). Their antioxidant and/or cancer chemopreventive properties support their interest in human health and therefore, the demand for their extraction. In the present study, ultrasound-assisted extraction (UAE) of flaxseed phenolic compounds was investigated. Scanning Electron Microscopy imaging and histochemical analysis revealed the deep alteration of the seedcoat ultrastructure and the release of the mucilage following ultrasound treatment. Therefore, this method was found to be very efficient for the reduction of mucilage entrapment of flaxseed phenolics. The optimal conditions for UAE phenolic compounds extraction from flaxseeds were found to be: water as solvent supplemented with 0.2N of sodium hydroxide for alkaline hydrolysis of the SDG-HMG complex, an extraction time of 60 min at a temperature of 25°C and an ultrasound frequency of 30 kHz. Under these optimized and validated conditions, highest yields of SDG, HDG and hydroxycinnamic acid glucosides were detected in comparison to other published methods. Therefore, the procedure presented herein is a valuable method for efficient extraction and quantification of the main flaxseed phenolics. Moreover, this UAE is of particular interest within the context of green chemistry in terms of reducing energy consumption and valuation of flaxseed cakes as by-products resulting from the production of flax oil.
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http://dx.doi.org/10.1016/j.ultsonch.2015.02.008DOI Listing
September 2015

Gadolinium-based contrast agents targeted to amyloid aggregates for the early diagnosis of Alzheimer's disease by MRI.

Eur J Med Chem 2014 Nov 8;87:843-61. Epub 2014 Oct 8.

Conservatoire national des arts et métiers, ERL 3193 Cnrs, 2 rue Conté, 75003 Paris, France.

While important efforts were made in the development of positron emission tomography (PET) tracers for the in vivo molecular diagnosis of Alzheimer's disease, very few investigations to develop magnetic resonance imaging (MRI) probes were performed. Here, a new generation of Gd(III)-based contrast agents (CAs) is proposed to detect the amyloid β-protein (Aβ) aggregates by MRI, one of the earliest biological hallmarks of the pathology. A building block strategy was used to synthesize a library of 16 CAs to investigate structure-activity relationships (SARs) on physicochemical properties and binding affinity for the Aβ aggregates. Three types of blocks were used to modulate the CA structures: (i) the Gd(III) chelates (Gd(III)-DOTA and Gd(III)-PCTA), (ii) the biovectors (2-arylbenzothiazole, 2-arylbenzoxazole and stilbene derivatives) and (iii) the linkers (neutrals, positives and negatives with several lengths). These investigations revealed unexpected SARs and a difficulty of these probes to cross the blood-brain barrier (BBB). General insights for the development of Gd(III)-based CAs to detect the Aβ aggregates are described.
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http://dx.doi.org/10.1016/j.ejmech.2014.10.016DOI Listing
November 2014

QSPR prediction of the stability constants of gadolinium(III) complexes for magnetic resonance imaging.

J Chem Inf Model 2014 Oct 18;54(10):2718-31. Epub 2014 Sep 18.

Laboratoire de Chimie moléculaire, génie des procédés chimiques et énergétiques (CMGPCE), Conservatoire national des arts et métiers (Cnam) , 2 rue Conté, 75003 Paris, France.

Gadolinium(III) complexes constitute the largest class of compounds used as contrast agents for Magnetic Resonance Imaging (MRI). A quantitative structure-property relationship (QSPR) machine-learning based method is applied to predict the thermodynamic stability constants of these complexes (log KGdL), a property commonly associated with the toxicity of such organometallic pharmaceuticals. In this approach, the log KGdL value of each complex is predicted by a graph machine, a combination of parametrized functions that encodes the 2D structure of the ligand. The efficiency of the predictive model is estimated on an independent test set; in addition, the method is shown to be effective (i) for estimating the stability constants of uncharacterized, newly synthesized polyamino-polycarboxylic compounds and (ii) for providing independent log KGdL estimations for complexants for which conflicting or questionable experimental data were reported. The exhaustive database of log KGdL values for 158 complexants, reported for potential application as contrast agents for MRI and used in the present study, is available in the Supporting Information (122 primary literature sources).
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http://dx.doi.org/10.1021/ci500346wDOI Listing
October 2014

Microwave-assisted extraction of herbacetin diglucoside from flax (Linum usitatissimum L.) seed cakes and its quantification using an RP-HPLC-UV system.

Molecules 2014 Mar 10;19(3):3025-37. Epub 2014 Mar 10.

Laboratoire de Biologie des Ligneux et des Grandes Cultures UPRES EA 1207, Equipe Lignanes des Linacées, Université d'Orléans - Antenne Scientifique Universitaire de Chartres, 21 rue de Loigny la Bataille, 28000 Chartres, France.

Flax (Linum usitatissimum L.) seeds are widely used for oil extraction and the cold-pressed flaxseed (or linseed) cakes obtained during this process constitute a valuable by-product. The flavonol herbacetin diglucoside (HDG) has been previously reported as a constituent of the flaxseed lignan macromolecule linked through ester bonds to the linker molecule hydroxymethylglutaric acid. In this context, the development and validation of a new approach using microwave-assisted extraction (MAE) of HDG from flaxseed cakes followed by quantification with a reverse-phase HPLC system with UV detection was purposed. The experimental parameters affecting the HDG extraction yield, such as microwave power, extraction time and sodium hydroxide concentration, from the lignan macromolecule were optimized. A maximum HDG concentration of 5.76 mg/g DW in flaxseed cakes was measured following an irradiation time of 6 min, for a microwave power of 150 W using a direct extraction in 0.1 M NaOH in 70% (v/v) aqueous methanol. The optimized method was proven to be rapid and reliable in terms of precision, repeatability, stability and accuracy for the extraction of HDG. Comparison with a conventional extraction method demonstrated that MAE is more effective and less time-consuming.
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http://dx.doi.org/10.3390/molecules19033025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270660PMC
March 2014

Microwave-assisted synthesis of prebiotic di-D-fructose dianhydride-enriched caramels.

Food Chem 2012 Oct 28;134(3):1527-32. Epub 2012 Mar 28.

Laboratoire de Génie des Procédés pour l'Environnement, l'Energie et la Santé (EA 21), Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.

The synthesis of prebiotic caramels involving the use of microwaves as the activating/heating source has been achieved. The yields in di-fructose dianhydrides (DFAs) in caramels were measured. The aim of this study was twofold: first to check the feasibility of the process, and second to determine the conditions to obtain an optimum response with microwave heating. The study showed that it was possible to obtain a yield of almost 50% of DFAs in a reaction time that was 10 times shorter than a previous study; i.e. 5-10 min for microwave activation compared to 60-120 min for conventional heating. It was shown that the radiation time and the radiation power were linked. The simultaneous determination of the values of these two factors was therefore necessary to obtain significant yields. This technique demonstrates the advantage of activation for mixtures such as caramels.
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http://dx.doi.org/10.1016/j.foodchem.2012.03.068DOI Listing
October 2012

Chemical and biochemical approaches to the production of 7-hydroxylated C19-steroids.

Horm Mol Biol Clin Investig 2012 Jun;10(3):293-9

Abstract Interest has developed into 7-hydroxylated derivatives of 3β-hydroxylated C19-steroids, such as dehydroepiandrosterone (DHEA) and epiandrosterone because of their effects on inflammation, immune response, and cell repair. These steroids are not currently available from commercial sources, and it is necessary to produce them for relevant studies. We report here the chemical and biochemical approaches that were used for their production. Simplified chemical approaches lead to the production of 7α-/7β-hydroxy-DHEA and 7β-hydroxy-epiandrosterone in gram quantities, which are made available to researchers. Biochemical approaches were used to produce isotope-labeled compounds. Thus, 2H-, 3H-, and 14C-labeled 7α-/7β-hydroxy-DHEA and 7β-hydroxy-epiandrosterone could be produced in quantities sufficient for use in investigations into their mode of action.
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http://dx.doi.org/10.1515/hmbci-2012-0013DOI Listing
June 2012

Cost-effectiveness of magnetic resonance imaging with a new contrast agent for the early diagnosis of Alzheimer's disease.

PLoS One 2012 20;7(4):e35559. Epub 2012 Apr 20.

Laboratoire Modélisation et Surveillance des risques sanitaires - Conservatoire national des Arts et Métiers - 75003, Paris, France.

Background: Used as contrast agents for brain magnetic resonance imaging (MRI), markers for beta-amyloid deposits might allow early diagnosis of Alzheimer's disease (AD). We evaluated the cost-effectiveness of such a diagnostic test, MRI+CLP (contrastophore-linker-pharmacophore), should it become clinically available.

Methodology/principal Findings: We compared the cost-effectiveness of MRI+CLP to that of standard diagnosis using currently available cognition tests and of standard MRI, and investigated the impact of a hypothetical treatment efficient in early AD. The primary analysis was based on the current French context for 70-year-old patients with Mild Cognitive Impairment (MCI). In alternative "screen and treat" scenarios, we analyzed the consequences of systematic screenings of over-60 individuals (either population-wide or restricted to the ApoE4 genotype population). We used a Markov model of AD progression; model parameters, as well as incurred costs and quality-of-life weights in France were taken from the literature. We performed univariate and probabilistic multivariate sensitivity analyses. The base-case preferred strategy was the standard MRI diagnosis strategy. In the primary analysis however, MRI+CLP could become the preferred strategy under a wide array of scenarios involving lower cost and/or higher sensitivity or specificity. By contrast, in the "screen and treat" analyses, the probability of MRI+CLP becoming the preferred strategy remained lower than 5%.

Conclusions/significance: It is thought that anti-beta-amyloid compounds might halt the development of dementia in early stage patients. This study suggests that, even should such treatments become available, systematically screening the over-60 population for AD would only become cost-effective with highly specific tests able to diagnose early stages of the disease. However, offering a new diagnostic test based on beta-amyloid markers to elderly patients with MCI might prove cost-effective.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035559PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332046PMC
August 2012

Rapid synthesis of new DNMT inhibitors derivatives of procainamide.

Chembiochem 2012 Jan 14;13(1):157-65. Epub 2011 Dec 14.

CNRS-MNHN UMR 7196 INSERM U565, Paris, France.

DNA methyltransferases (DNMTs) are responsible for DNA methylation, an epigenetic modification involved in gene regulation. Families of conjugates of procainamide, an inhibitor of DNMT1, were conceived and produced by rapid synthetic pathways. Six compounds resulted in potent inhibitors of the murine catalytic Dnmt3A/3L complex and of human DNMT1, at least 50 times greater than that of the parent compounds. The inhibitors showed selectivity for C5 DNA methyltransferases. The cytotoxicity of the inhibitors was validated on two tumour cell lines (DU145 and HCT116) and correlated with the DNMT inhibitory potency. The inhibition potency of procainamide conjugated to phthalimide through alkyl linkers depended on the length of the linker; the dodecane linker was the best.
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http://dx.doi.org/10.1002/cbic.201100522DOI Listing
January 2012

Synthesis of a 19-(O-carboxymethyl)oxime hapten of 7β-hydroxy-epiandrosterone.

Horm Mol Biol Clin Investig 2011 Oct;7(1):295-301

In order to develop an immunoassay of 7β-hydroxy-epiandrosterone, a stereoselective synthesis of a specific hapten, 7β-hydroxy-19-oxo-androstan 19-(O-carboxymethyl)oxime (17), was performed. This synthesis was achieved in 16% overall yield starting from the well-known 3β-acetoxy-19-hydroxy-5-androsten-17-one (1). After coupling of the alkyl oxime moiety, an allylic oxidation of the C-7 carbon under mild conditions followed by two selective reductions established all the functionalities of the final compound 17.
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http://dx.doi.org/10.1515/HMBCI.2011.108DOI Listing
October 2011

X-ray photolysis to release ligands from caged reagents by an intramolecular antenna sensitive to magnetic resonance imaging.

Angew Chem Int Ed Engl 2011 Oct 21;50(41):9708-11. Epub 2011 Jul 21.

Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris-Descartes, France.

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http://dx.doi.org/10.1002/anie.201102948DOI Listing
October 2011

Podophyllotoxin and deoxypodophyllotoxin in Juniperus bermudiana and 12 other Juniperus species: optimization of extraction, method validation, and quantification.

J Agric Food Chem 2011 Aug 15;59(15):8101-7. Epub 2011 Jul 15.

Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC), UPRES EA 1207, Antenne Scientifique Universitaire de Chartres (ASUC), Université d'Orléans, Chartres, France.

The lignans podophyllotoxin and deoxypodophyllotoxin are secondary metabolites with potent pharmaceutical applications in cancer therapy. However, the supply of podophyllotoxin from its current natural source, Podophyllum hexandrum, is becoming increasingly problematic, and alternative sources are therefore urgently needed. So far, podophyllotoxin and deoxypodophyllotoxin have been found in some Juniperus species, although at low levels in most cases. Moreover, extraction protocols deserve optimization. This study aimed at developing and validating an efficient extraction protocol of podophyllotoxin and deoxypodophyllotoxin from Juniperus species and applying it to 13 Juniperus species, among which some had never been previously analyzed. Juniperus bermudiana was used for the development and validation of an extraction protocol for podophyllotoxin and deoxypodophyllotoxin allowing extraction yields of up to 22.6 mg/g DW of podophyllotoxin and 4.4 mg/g DW deoxypodophyllotoxin, the highest values found in leaf extract of Juniperus. The optimized extraction protocol and HPLC separation from DAD or MS detections were established and validated to investigate podophyllotoxin and deoxypodophyllotoxin contents in aerial parts of 12 other Juniperus species. This allowed either higher yields to be obtained in some species reported to contain these two compounds or the occurrence of these compounds in some other species to be reported for the first time. This efficient protocol allows effective extraction of podophyllotoxin and deoxypodophyllotoxin from aerial parts of Juniperus species, which could therefore constitute interesting alternative sources of these valuable metabolites.
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http://dx.doi.org/10.1021/jf201410pDOI Listing
August 2011

Synthesis of 7β-hydroxy-epiandrosterone.

Steroids 2011 Jan 19;76(1-2):28-30. Epub 2010 Aug 19.

Laboratoire de Transformations Chimiques et Pharmaceutiques, UMR7084, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.

The synthesis of 7β-hydroxy-epiandrosterone (6) possessing strong anti-inflammatory properties was achieved starting from 3β-acetoxy-17,17-(ethylenedioxy)-5-androsten (1). This approach involved as a main step an allylic oxidation of the C-7 followed by two reduction reactions of the double bond and of the carbonyl group. This stereoselective synthesis in 5 steps gave 7β-hydroxy-epiandrosterone in 63% overall yield.
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http://dx.doi.org/10.1016/j.steroids.2010.08.003DOI Listing
January 2011

Epimerase activity of the human 11beta-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids.

J Steroid Biochem Mol Biol 2009 Mar 9;114(1-2):57-63. Epub 2009 Jan 9.

Chaire de Génie Biologique, EA-3199, Biotechnologie, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.

Cytochrome P4507B1 7alpha-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5alpha-androstane-3beta,17beta-diol (Adiol). 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts 7alpha- and 7beta-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [(3)H]-labelled 7beta-hydroxy-DHEA, 7beta-hydroxy-EpiA and 7beta-hydroxy-Adiol showed the (3)H-label to accumulate in the 7-oxo-DHEA trap but not in 7-oxo-EpiA or 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids docked in the active site of 11beta-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7alpha- or 7beta-hydroxylated derivatives resulted from either turned or flipped forms. 11beta-HSD1 incubation in H(2)(18)O medium with each 7-hydroxysteroid did not incorporate (18)O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7alpha- and 7beta-hydroxy-DHEA through 7-oxo-DHEA. Epimerization may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser(170). The physiopathological importance of this epimerization process is related to 7beta-hydroxy-EpiA production and its effects in triggering the resolution of inflammation.
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http://dx.doi.org/10.1016/j.jsbmb.2008.12.015DOI Listing
March 2009

7alpha- and 7beta-hydroxy-epiandrosterone as substrates and inhibitors for the human 11beta-hydroxysteroid dehydrogenase type 1.

J Steroid Biochem Mol Biol 2007 Jun-Jul;105(1-5):159-65. Epub 2007 May 17.

Chaire de Génie Biologique, EA-3199, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.

The human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes both the NADP(H)-dependent oxido-reduction of cortisol and cortisone and the inter-conversion of 7alpha- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) through a 7-oxo-DHEA intermediate. As shown with human liver and intestine fractions, 7alpha-hydroxy-epiandrosterone (7alpha-hydroxy-EpiA) and 7beta-hydroxy-EpiA were readily inter-converted with no evidence for a 7-oxo-EpiA intermediate. Whether this inter-conversion resulted from action of the 11beta-HSD1 or from an unknown epimerase is unresolved. Furthermore, whether these steroids could inhibit the cortisol-cortisone oxido-reduction remains a question. The recombinant human 11beta-HSD1 was used to test these questions. NADP(+) supplementation only provided the production of 7beta-hydroxy-EpiA out of 7alpha-hydroxy-EpiA with a V(max)/K(M) ratio at 0.1. With NADPH supplementation, both 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA were formed in low amounts from 7beta-hydroxy-EpiA and 7alpha-hydroxy-EpiA, respectively. These inter-conversions occurred without a trace of the putative 7-oxo-EpiA intermediate. In contrast, the 7-oxo-EpiA substrate was efficiently reduced into 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA, with V(max)/K(M) ratios of 23.6 and 5.8, respectively. Competitive and mixed type inhibitions of the 11beta-HSD1-mediated cortisol oxidation were exerted by 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA, respectively. The 11beta-HSD1-mediated cortisone reduction was inhibited in a competitive manner by 7-oxo-EpiA. These findings suggest that the active site of the human 11beta-HSD1 may carry out directly the epimeric transformation of 7-hydroxylated EpiA substrates. The low amounts of these steroids in human do not support a physiological importance for modulation of the glucocorticoid status in tissues.
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http://dx.doi.org/10.1016/j.jsbmb.2006.11.021DOI Listing
November 2007

Impact of rigidification on relaxometric properties of a tricyclic tetraazatriacetic gadolinium chelate.

Contrast Media Mol Imaging 2006 May-Jun;1(3):121-7

Guerbet, Centre de Recherche, BP 57400, 95943 Roissy CdG Cedex, France.

A constrained derivative of Gd-PCTA12, Gd-cyclo-PCTA12, in which one ethylene bridge connecting two nitrogen atoms of the triamine block is replaced by a cyclohexylene bridge, was synthesized and the impact of rigidification was studied by comparing the physicochemical and relaxometric properties of both gadolinium MRI contrast agents, Gd-PCTA12 and Gd-cyclo-PCTA12. The new complex has higher proton relaxivity than the parent compound (r(1) = 6.1 s(-1) mM(-1) at 20 MHz and 310 K). The rigidification of the PCTA12 scaffold proved to have no impact on the inertness towards transmetallation by endogenous ions such as Zn(2+). Moreover, for both contrast agents, the relaxivity was not quenched by endogenous anions. The oxygen-17 NMR study and the NMRD profile demonstrated that the rigidification of the PCTA scaffold had no impact on the electronic relaxation of Gd-cyclo-PCTA12. However, the rigidity of this complex induced an acceleration of the exchange rate of the inner-sphere water molecules as a result of steric crowding around the gadolinium ion. The value of tau(M) (310) thus approached the optimal value required to attain high relaxivity once the chelate is immobilized by covalent or non-covalent binding to macromolecules.
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http://dx.doi.org/10.1002/cmmi.99DOI Listing
March 2007
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