Publications by authors named "Florence Souard"

28 Publications

  • Page 1 of 1

Coffee Leaves: An Upcoming Novel Food?

Planta Med 2021 Sep 24. Epub 2021 Sep 24.

RD3 Department-Unit of Pharmacognosy, Bioanalysis and Drug Discovery, Faculty of Pharmacy, Université libre de Bruxelles, Brussels, Belgium.

Unlike those of coffee beans, the healthy properties of coffee leaves have been overlooked for a long time, even if they are consumed as a beverage by local communities of several African countries. Due to the presence of xanthines, diterpenes, xanthones, and several other polyphenol derivatives as main secondary metabolites, coffee leaves might be useful to prevent many daily disorders. At the same time, as for all bioactive molecules, careless use of coffee leaf infusions may be unsafe due to their adverse effects, such as the excessive stimulant effects on the central nervous system or their interactions with other concomitantly administered drugs. Moreover, the presence of some toxic diterpene derivatives requires careful analytical controls on manufactured products made with coffee leaves. Accordingly, knowledge about the properties of coffee leaves needs to be increased to know if they might be considered a good source for producing new supplements. The purpose of the present review is to highlight the biosynthesis, metabolism, and distribution of the 4 main classes of secondary metabolites present in coffee leaves, their main pharmacological and toxicological aspects, and their main roles . Differences in coffee leaf chemical composition depending on the coffee species will also be carefully considered.
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http://dx.doi.org/10.1055/a-1533-0021DOI Listing
September 2021

Untargeted metabolomics approach to discriminate mistletoe commercial products.

Sci Rep 2021 07 9;11(1):14205. Epub 2021 Jul 9.

Univ. Grenoble Alpes, CNRS, DPM, 38000, Grenoble, France.

Mistletoe (Viscum album L.) is used in German-speaking European countries in the field of integrative oncology linking conventional and complementary medicine therapies to improve quality of life. Various companies sell extracts, fermented or not, for injection by subcutaneous or intra-tumoral route with a regulatory status of anthroposophic medicinal products (European Medicinal Agency (EMA) assessment status). These companies as well as anthroposophical physicians argue that complex matrices composed of many molecules in mixture are necessary for activity and that the host tree of the mistletoe parasitic plant is the main determining factor for this matrix composition. The critical point is that parenteral devices of European mistletoe extracts do not have a standard chemical composition regulated by EMA quality guidelines, because they are not drugs, regulatory speaking. However, the mechanism of mistletoe's anticancer activity and its effectiveness in treating and supporting cancer patients are not fully understood. Because of this lack of transparency and knowledge regarding the matrix chemical composition, we undertook an untargeted metabolomics study of several mistletoe extracts to explore and compare their fingerprints by LC-(HR)MS(/MS) and H-NMR. Unexpectedly, we showed that the composition was primarily driven by the manufacturer/preparation method rather than the different host trees. This differential composition may cause differences in immunostimulating and anti-cancer activities of the different commercially available mistletoe extracts as illustrated by structure-activity relationships based on LC-MS/MS and H-NMR identifications completed by docking experiments. In conclusion, in order to move towards an evidence-based medicine use of mistletoe, it is a priority to bring rigor and quality, chemically speaking.
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http://dx.doi.org/10.1038/s41598-021-93255-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270909PMC
July 2021

Antibacterial Activities of Homemade Matrices Miming Essential Oils Compared to Commercial Ones.

Antibiotics (Basel) 2021 May 14;10(5). Epub 2021 May 14.

Department of Pharmacotherapy and Pharmaceutics (DPP), Pharmacology, Pharmacotherapy and Pharmaceutical Care Unit, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium.

The increasing bacterial resistance to antibiotics is a worldwide concern. Essential oils are known to possess remarkable antibacterial properties, but their high chemical variability complicates their development into new antibacterial agents. Therefore, the main purpose of this study was to standardize their chemical composition. Several commercial essential oils of ajowan ( L.) and thyme (chemotype thymol) ( L.) were bought on the market. GC-MS analysis revealed that thyme essential oils have a chemical composition far more consistent than ajowan essential oils. Sometimes thymol was not even the major compound. The most abundant compounds and the homemade mixtures were tested against two strains. The antibacterial property of -caryophyllene presented no direct activity against LMG 15975, but in association with thymol or carvacrol at equal percentages an MIC of 125 μg/mL was observed. The mixture of those three compounds at equivalent percentages also decreased by 16-fold the MIC of the penicillin V. Against LMG 21674, -caryophyllene presented an MIC of 31.3 μg/mL and decreased by 267-fold the MIC of the penicillin V. These observations led us to question the benefits of using a complex chemical mixture instead of one active compound to fight bacterial resistance.
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http://dx.doi.org/10.3390/antibiotics10050584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156816PMC
May 2021

Proposals for Antimicrobial Testing Guidelines Applied on Ajowan and Spanish Lavender Essential Oils.

Planta Med 2021 Aug 21;87(10-11):754-763. Epub 2021 Apr 21.

Department of Pharmacotherapy and Pharmaceutics (DPP), Pharmacology, Pharmacotherapy and Pharmaceutical care Unit, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Brussels, Belgium.

To fight the rising resistance of microorganisms to antibiotics, a strategy followed by several researchers is to focus on natural compounds, such as essential oils, as a source of potent antibacterial compounds. These last decades, hundreds of original papers have been written about microbiological assays that prove the antibacterial activity of essential oils and their use in the medical field. But can we really compare all the data available in the literature when the raw material, the microbiological assays, and/or the strains are different from one article to another? This review will point out the differences and the inadequate practices found in published articles that tested 2 lesser-studied essential oils-Spanish lavender and the ajowan-by the broth dilution method against , a human pathogenic bacterium. Many pitfalls were found in the literature, for example, a variable chemical composition rarely underlined by the authors, unidentified strains or clinical strains used without a related antibiogram, a lack of quality controls, and the assertion of questionable positive results. At last, some general guidelines that should be followed by every scientific researcher will be discussed.
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http://dx.doi.org/10.1055/a-1475-0020DOI Listing
August 2021

Does the Phytochemical Diversity of Wild Plants Like the Correlate with Geographical Origin?

Molecules 2021 Mar 17;26(6). Epub 2021 Mar 17.

Département de Pharmacochimie Moléculaire (DPM), Univiversité Grenoble Alpes, CNRS, 38000 Grenoble, France.

Secondary metabolites are essential for plant survival and reproduction. Wild undomesticated and tropical plants are expected to harbor highly diverse metabolomes. We investigated the metabolomic diversity of two morphologically similar trees of tropical Africa, and , known for particular secondary metabolites named the cassaine-type diterpenoids. To assess how the metabolome varies between and within species, we sampled leaves from individuals of different geographic origins but grown from seeds in a common garden in Cameroon. Metabolites were analyzed using reversed phase LC-HRMS(/MS). Data were interpreted by untargeted metabolomics and molecular networks based on MS/MS data. Multivariate analyses enabled us to cluster samples based on species but also on geographic origins. We identified the structures of 28 cassaine-type diterpenoids among which 19 were new, 10 were largely specific to and five to . Our results showed that the metabolome allows an unequivocal distinction of morphologically-close species, suggesting the potential of metabolite fingerprinting for these species. Plant geographic origin had a significant influence on relative concentrations of metabolites with variations up to eight () and 30 times () between origins of the same species. This shows that the metabolome is strongly influenced by the geographical origin of plants (i.e., genetic factors).
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http://dx.doi.org/10.3390/molecules26061668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002556PMC
March 2021

Antibacterial and Cytotoxic Activities of Ten Commercially Available Essential Oils.

Antibiotics (Basel) 2020 Oct 20;9(10). Epub 2020 Oct 20.

Department of Pharmacotherapy and Pharmaceutics (DPP), Pharmacology, Pharmacotherapy and Pharmaceutical care Unit, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, Belgium.

There is a huge concern in the medical field concerning the emergence of bacterial resistance to antibiotics. Essential oils are a source of antibacterial compounds that can overcome this problem. Ten essential oils that are commercially available were investigated in the present study: ajowan, basil, German chamomile, Chinese cinnamon, coriander, clove, lemongrass, Spanish lavender, oregano and palmarosa. Their direct, synergistic and indirect antibacterial activities were evaluated against different human pathogenic Gram-positive and Gram-negative strains. To evaluate their possible use in clinics, the cytotoxicity of these essential oils was also tested on keratinocyte and epithelial cell lines. Except for the Chinese cinnamon, coriander and lemongrass, all other essential oils presented no cytotoxicity at 32 and 16 μg/mL. The highest indirect antibacterial activities were observed with the palmarosa and Spanish lavender in association with penicillin V. These two associations presented a 64-fold decrease against a resistant strain of , however, at a cytotoxic concentration. It can also be highlighted that when tested at a non-cytotoxic concentration, the activity of oregano in association with penicillin V presented an eight-fold decrease. These results show the interest to use essential oils in combination with antibiotics to reduce their concentrations inside drugs.
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http://dx.doi.org/10.3390/antibiotics9100717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589993PMC
October 2020

Two in one: bifunctional derivatives of trolox acting as antimalarial and antioxidant agents.

Future Med Chem 2020 10 9;12(20):1845-1854. Epub 2020 Oct 9.

Département de Pharmacochimie Moléculaire, Univ. Grenoble Alpes, CNRS, DPM UMR 5063, F-38041, Grenoble, France.

The aim of the present work was to set-up compounds that are able to act simultaneously as antimalarial and antioxidants. Trolox, a known antioxidant was chosen as a core structure to ensure the antioxidant activity and contribute to antiplasmodial effect. Ten compounds were prepared in one step and evaluated on chloroquino-sensitive (3D7) and chloroquino-resistant (FcB1) strains of . The most active compound () shows antiplasmodial activity in the range of chloroquine against chloroquino-sensitive and chloroquino-resistant strain. The antioxidant activity of () was conducted through four tests and was found to be more potent than trolox itself and L-ascorbic acid. Compound () can be considered as an excellent lead molecule for further studies. This study paves the way for building large chemical libraries to be investigated in the field of malaria.
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http://dx.doi.org/10.4155/fmc-2020-0106DOI Listing
October 2020

Mistletoe-Extract Drugs Stimulate Anti-Cancer Vγ9Vδ2 T Cells.

Cells 2020 06 26;9(6). Epub 2020 Jun 26.

Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles (ULB), 1050 Bruxelles, Belgium.

Human phosphoantigen-reactive Vγ9Vδ2 T cells possess several characteristics, including MHC-independent recognition of tumor cells and potent killing potential, that make them attractive candidates for cancer immunotherapeutic approaches. Injectable preparations from the hemi-parasite plant L. (European mistletoe) are commonly prescribed as complementary cancer therapy in European countries such as Germany, but their mechanism of action remains poorly understood. Here, we investigated in-depth the in vitro response of human T cells towards mistletoe-extract drugs by analyzing their functional and T-cell-receptor (TCR) response using flow cytometry and high-throughput sequencing respectively. Non-fermented mistletoe-extract drugs (AbnobaViscum), but not their fermented counterparts (Iscador), induced specific expansion of Vγ9Vδ2 T cells among T cells. Furthermore, AbnobaViscum rapidly induced the release of cytotoxic granules and the production of the cytokines IFNγ and TNFα in Vγ9Vδ2 T cells. This stimulation of anti-cancer Vγ9Vδ2 T cells was mediated by the butyrophilin BTN3A, did not depend on the accumulation of endogenous phosphoantigens and involved the same Vγ9Vδ2 TCR repertoire as those of phosphoantigen-reactive Vγ9Vδ2 T cells. These insights highlight Vγ9Vδ2 T cells as a potential target for mistletoe-extract drugs and their role in cancer patients receiving these herbal drugs needs to be investigated.
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http://dx.doi.org/10.3390/cells9061560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349316PMC
June 2020

A new potential anti-cancer beta-carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation.

Drug Dev Res 2020 02 9;81(1):32-42. Epub 2019 Sep 9.

Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.

Gliomas remain highly fatal due to their high resistance to current therapies. Deregulation of protein synthesis contributes to cancer onset and progression and is a source of rising interest for new drugs. CM16, a harmine derivative with predicted high blood-brain barrier penetration, exerts antiproliferative effects partly through translation inhibition. We evaluated herein how CM16 alters the proteome of glioma cells. The analysis of the gel-free LC/MS and auto-MS/MS data showed that CM16 induces time- and concentration-dependent significant changes in the total ion current chromatograms. In addition, we observed spontaneous clustering of the samples according to their treatment condition and their proper classification by unsupervised and supervised analyses, respectively. A two-dimensional gel-based approach analysis allowed us to identify that treatment with CM16 may downregulate four key proteins involved in glioma aggressiveness and associated with poor patient survival (HspB1, BTF3, PGAM1, and cofilin), while it may upregulate galectin-1 and Ebp1. Consistently with the protein synthesis inhibition properties of CM16, HspB1, Ebp1, and BTF3 exert known roles in protein synthesis. In conclusion, the downregulation of HspB1, BTF3, PGAM1 and cofilin bring new insights in CM16 antiproliferative effects, further supporting CM16 as an interesting protein synthesis inhibitor to combat glioma.
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http://dx.doi.org/10.1002/ddr.21600DOI Listing
February 2020

Determination of Three Main Chlorogenic Acids in Water Extracts of Coffee Leaves by Liquid Chromatography Coupled to an Electrochemical Detector.

Antioxidants (Basel) 2018 Oct 15;7(10). Epub 2018 Oct 15.

Bioanalysis and Drug Discovery, RD3-Unit of Pharmacognosy, Faculty of Pharmacy, Université libre de Bruxelles, Campus Plaine CP 205/6, 1050 Brussels, Belgium.

Coffee is a beverage widely consumed in the world. The coffee species most commercialized worldwide are Arabica ( and Robusta (. Roasted coffee beans are the most used, but coffee leaves are also consumed as infusion in several countries for traditional medicinal purposes. They contain several interesting phenolic antioxidant compounds mainly belonging to chlorogenic acids (CGAs). In the present work, a liquid chromatography-electrochemical detection (LC-EC) method was developed for the determination of three main chlorogenic acid isomers, namely 3-, 4-, and 5-caffeoylquinic acids (CQA), in coffee leaves aqueous extracts. Samples from eight coffee species, namely; , , , , , , , and , were grown and collected in tropical greenhouses. Linearity of the calibration graphs was observed in the range from the limit of quantification to 1.0 × 10 M, with R² equal to 99.9% in all cases. High sensitivity was achieved with a limit of detection of 1.0 × 10 M for 3-CQA and 5-CQA (i.e., 3.5 µg/L) and 2.0 × 10 M for 4-CQA (i.e., 7.1 µg/L). The chromatographic profile of the samples harvested for each species was studied comparatively. Obtained raw data were pretreated for baseline variations and shifts in retention times between the chromatographic profiles. Principal Component Analysis (PCA) was applied to the pretreated data. According to the results, three clusters of species were found. In the water sample extracts, 5-CQA appeared to be the major isomer, and some species contained a very low amount of CQAs. Fluctuations were observed depending on the species and harvesting period. Significant differences between January and July were noticed regarding CQAs content. The species with the best CQAs/caffeine ratio was identified. The LC-EC data were validated by liquid chromatography-high resolution mass spectrometry (LC-HRMS).
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http://dx.doi.org/10.3390/antiox7100143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209918PMC
October 2018

Contrasting cadmium resistance strategies in two metallicolous populations of Arabidopsis halleri.

New Phytol 2018 04 2;218(1):283-297. Epub 2018 Jan 2.

Laboratory of Plant Physiology and Molecular Genetics, Université Libre de Bruxelles, 1050, Brussels, Belgium.

While cadmium (Cd) tolerance is a constitutive trait in the Arabidopsis halleri species, Cd accumulation is highly variable. Recent adaptation to anthropogenic metal stress has occurred independently within the genetic units of A. halleri and the evolution of different mechanisms involved in Cd tolerance and accumulation has been suggested. To gain a better understanding of the mechanisms underlying Cd tolerance and accumulation in A. halleri, ionomic inductively coupled plasma mass spectrometry (ICP-MS), transcriptomic (RNA sequencing) and metabolomic (high-performance liquid chromatography-mass spectrometry) profiles were analysed in two A. halleri metallicolous populations from different genetic units (PL22 from Poland and I16 from Italy). The PL22 and I16 populations were both hypertolerant to Cd, but PL22 hyperaccumulated Cd while I16 behaved as an excluder both in situ and when grown hydroponically. The observed hyperaccumulator vs excluder behaviours were paralleled by large differences in the expression profiles of transporter genes. Flavonoid-related transcripts and metabolites were strikingly more abundant in PL22 than in I16 shoots. The role of novel A. halleri candidate genes possibly involved in Cd hyperaccumulation or exclusion was supported by the study of corresponding A. thaliana knockout mutants. Taken together, our results are suggestive of the evolution of divergent strategies for Cd uptake, transport and detoxification in different genetic units of A. halleri.
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http://dx.doi.org/10.1111/nph.14948DOI Listing
April 2018

Metabolomics fingerprint of coffee species determined by untargeted-profiling study using LC-HRMS.

Food Chem 2018 Apr 12;245:603-612. Epub 2017 Oct 12.

Laboratoire de Pharmacognosie, de Bromatologie et de Nutrition Humaine, Faculté de Pharmacie, Université Libre de Bruxelles, Campus Plaine, CP 205/09, 1050 Brussels, Belgium.

Coffee bean extracts are consumed all over the world as beverage and there is a growing interest in coffee leaf extracts as food supplements. The wild diversity in Coffea (Rubiaceae) genus is large and could offer new opportunities and challenges. In the present work, a metabolomics approach was implemented to examine leaf chemical composition of 9 Coffea species grown in the same environmental conditions. Leaves were analyzed by LC-HRMS and a comprehensive statistical workflow was designed. It served for univariate hypothesis testing and multivariate modeling by PCA and partial PLS-DA on the Workflow4Metabolomics infrastructure. The first two axes of PCA and PLS-DA describes more than 40% of variances with good values of explained variances. This strategy permitted to investigate the metabolomics data and their relation with botanic and genetic informations. Finally, the identification of several key metabolites for the discrimination between species was further characterized.
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http://dx.doi.org/10.1016/j.foodchem.2017.10.022DOI Listing
April 2018

Identification of coffee leaves using FT-NIR spectroscopy and SIMCA.

Talanta 2018 Jan 23;177:4-11. Epub 2017 Sep 23.

Laboratory of Instrumental Analysis and Bioelectrochemistry, Faculty of Pharmacy, Université Libre de Bruxelles, Boulevard du Triomphe, Campus Plaine, CP 205/06, 1050, Brussels, Belgium.

Abundant literature has been devoted to coffee beans (green or roasted) chemical description but relatively few studies have been devoted to coffee leaves. Given the fact that coffee leaves are used for food and medicinal consumption, it was of interest to develop a rapid screening method in order to identify coffee leaves taxa. Investigation by Fourier - Transform near infrared spectroscopy (FT-NIRS) was performed on nine Coffea taxa leaves harvested over one year in a tropical greenhouse of the Botanic Garden Meise (Belgium). The only process after leaves harvesting was an effective drying and a homogeneous leaves grinding. FT-NIRS with SIMCA analysis allowed to discriminate the spectral profiles across taxon, aging stage (mature and senescence coffee leaves) and harvest period. This study showed that it was possible (i) to classify the different taxa, (ii) to identify their aging stage and (iii) to identify the harvest period for the mature stage with a correct classification rate of 99%, 100% and 90%, respectively.
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http://dx.doi.org/10.1016/j.talanta.2017.09.056DOI Listing
January 2018

Terpenoids from Platostoma rotundifolium (Briq.) A. J. Paton Alter the Expression of Quorum Sensing-Related Virulence Factors and the Formation of Biofilm in Pseudomonas aeruginosa PAO1.

Int J Mol Sci 2017 Jun 14;18(6). Epub 2017 Jun 14.

Laboratoire de Pharmacognosie, Bromatologie et Nutrition Humaine, Faculté de Pharmacie, Université Libre de Bruxelles, CP 205/09, Boulevard du Triomphe, 1050 Bruxelles, Belgium.

(Briq.) A. J. Paton aerial parts are widely used in Burundi traditional medicine to treat infectious diseases. In order to investigate their probable antibacterial activities, crude extracts from P. rotundifolium were assessed for their bactericidal and anti-virulence properties against an opportunistic bacterial model, PAO1. Whereas none of the tested extracts exert bacteriostatic and/or bactericidal proprieties, the ethyl acetate and dichloromethane extracts exhibit anti-virulence properties against PAO1 characterized by an alteration in quorum sensing gene expression and biofilm formation without affecting bacterial viability. Bioguided fractionation of the ethyl acetate extract led to the isolation of major anti-virulence compounds that were identified from nuclear magnetic resonance and high-resolution molecular spectroscopy spectra as cassipourol, β-sitosterol and α-amyrin. Globally, cassipourol and β-sitosterol inhibit quorum sensing-regulated and -regulatory genes expression in las and rhl systems without affecting the global regulators gacA and vfr, whereas α-amyrin had no effect on the expression of these genes. These terpenoids disrupt the formation of biofilms at concentrations down to 12.5, 50 and 50 µM for cassipourol, β-sitosterol and α-amyrin, respectively. Moreover, these terpenoids reduce the production of total exopolysaccharides and promote flagella-dependent motilities (swimming and swarming). The isolated terpenoids exert a wide range of inhibition processes, suggesting a complex mechanism of action targeting virulence mechanisms which support the wide anti-infectious use of this plant species in traditional Burundian medicine.
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http://dx.doi.org/10.3390/ijms18061270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486092PMC
June 2017

Optimization of Experimental Parameters to Explore Small-Ligand/Aptamer Interactions through Use of (1) H NMR Spectroscopy and Molecular Modeling.

Chemistry 2015 Oct 10;21(44):15740-8. Epub 2015 Sep 10.

DPM, Université Grenoble Alpes, Grenoble, 38000 (France).

Aptamers constitute an emerging class of molecules designed and selected to recognize any given target that ranges from small compounds to large biomolecules, and even cells. However, the underlying physicochemical principles that govern the ligand-binding process still have to be clarified. A major issue when dealing with short oligonucleotides is their intrinsic flexibility that renders their active conformation highly sensitive to experimental conditions. To overcome this problem and determine the best experimental parameters, an approach based on the design-of-experiments methodology has been developed. Here, the focus is on DNA aptamers that possess high specificity and affinity for small molecules, L-tyrosinamide, and adenosine monophosphate. Factors such as buffer, pH value, ionic strength, Mg(2+) -ion concentration, and ligand/aptamer ratio have been considered to find the optimal experimental conditions. It was then possible to gain new insight into the conformational features of the two ligands by using ligand-observed NMR spectroscopic techniques and molecular mechanics.
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http://dx.doi.org/10.1002/chem.201501527DOI Listing
October 2015

Use of a fractional factorial design to study the effects of experimental factors on the chitin deacetylation.

Int J Biol Macromol 2014 Sep 2;70:385-90. Epub 2014 Jul 2.

Laboratory of Enzyme Engineering and Microbiology, National School of Engineering, PO Box 1173-3038, Sfax, Tunisia.

Chitosan is obtained by deacetylation of chitin. Chitosan versatility is directly related to the polymer's characteristics depending on the deacetylation process. The aim of this research was to study the parameters influencing deacetylation and to elucidate their effect on acetylation degree (DA) and molecular weight (MW). The effect on chitosan DA was investigated using a fractional factorial design 2(7-3) with seven factors and two variation levels. The tested factors were: X1=number of successive baths, X2=reaction time, X3=temperature, X4=alkali reagent, X5=sodium borohydride, X6=the atmospheric conditions and X7=alkali concentration. A mathematical model was investigated corresponding to the following relation ŷ=7.469-1.344X1-1.094X2-3.094X3+1.906X4+0.656X5+0.906X6-1.031X7+0.469X1X2-0.781X3X4+0.906X1X3X4 with R2=0.99. This model allows fixing experimental conditions for each desired DA. To study the effect on chitosan MW, only atmospheric conditions and use of sodium borohydride as an oxygen scavenger were investigated. The use of sodium borohydride and nitrogen atmosphere was found to have a protective effect against chitosan degradation during deacetylation.
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http://dx.doi.org/10.1016/j.ijbiomac.2014.06.051DOI Listing
September 2014

Pro-oxidant properties of indolone-N-oxides in relation to their antimalarial properties.

J Inorg Biochem 2013 Sep 29;126:7-16. Epub 2013 Apr 29.

Université de Toulouse, UPS, UMR 152 PHARMA-DEV, 118 route de Narbonne, F-31062 Toulouse cedex 9, France.

Indolone-N-oxides (INODs) are bioreducible and possess remarkable anti-malarial activities in the low nanomolar range in vitro against different Plasmodium falciparum (P. falciparum) strains and in vivo. INODs have an original mechanism of action: they damage the host cell membrane without affecting non-parasitized erythrocytes. These molecules produce a redox signal which activates SYK tyrosine kinases and induces a hyperphosphorylation of AE1 (band 3, erythrocyte membrane protein). The present work aimed to understand the early stages of the biochemical interactions of these compounds with some erythrocyte components from which the redox signal could originate. The interactions were studied in a biomimetic model and compared with those of chloroquine and artemisinin. The results showed that INODs i) do not enter the coordination sphere of the metal in the heme iron complex as does chloroquine; ii) do not generate iron-dependent radicals as does artemisinin; iii) generate stable free radical adducts after reduction at one electron; iv) cannot trap free radicals after reduction. These results confirm that the bioactivity of INODs does not lie in their spin-trapping properties but rather in their pro-oxidant character. This property may be the initiator of the redox signal which activates SYK tyrosine kinases.
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http://dx.doi.org/10.1016/j.jinorgbio.2013.04.012DOI Listing
September 2013

Potential of autochthonous fungal strains isolated from contaminated soils for degradation of polychlorinated biphenyls.

Fungal Biol 2013 Apr 14;117(4):268-74. Epub 2013 Mar 14.

Laboratoire d'Ecologie Alpine, UMR 5553 CNRS, Université Joseph Fourier, Grenoble 1, Grenoble Cedex 9, France.

Up to now, most studies on polychlorinated biphenyl (PCB) bioremediation have examined the ability of model fungal strains to biodegrade PCBs. Yet, there is limited information concerning the potential of autochthonous filamentous fungal strains in the biodegradation of PCBs and their possible use in the environmental technologies. In this study, we investigated the capacity of autochthonous fungal strains in the biodegradation of PCBs by isolating 24 taxa from former industrial sites highly contaminated by PCBs. Microscopic and molecular analyses using the internal transcribed spacer (ITS) region revealed that the fungal strains belonged to the phyla Ascomycota (19 strains) and Zygomycota (five strains). The chromatography gas analysis revealed evidence of degradation of seven PCB congeners. With the exception of Circinella muscae which presented no degradation potential, the other fungal strains exhibited a rate of biodegradation ranging from 29 to 85 % after 7 d of incubation in liquid medium. Among these strains, Doratomyces nanus, Doratomyces purpureofuscus, Doratomyces verrucisporus, Myceliophthora thermophila, Phoma eupyrena, and Thermoascus crustaceus showed remarkable degradation ability (>70 %) regardless of the number of chlorine substituents on the biphenyl nucleus and a high tolerance towards PCBs. To our knowledge, this is the first study that demonstrates the ability of PCB degradation by these species and indicates the potential effectiveness of some autochthonous fungal strains in bioremediation systems.
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http://dx.doi.org/10.1016/j.funbio.2013.02.004DOI Listing
April 2013

Sugar-oligoamides: synthesis of DNA minor groove binders.

J Org Chem 2012 Dec 16;77(23):10870-81. Epub 2012 Nov 16.

Departamento de Síntesis, Estructura y Propiedades de los Compuestos Orgánicos, Instituto de Química Orgánica General, CSIC, c/Juan de la Cierva 3, 28006 Madrid, Spain.

Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydrate-minor groove DNA interactions. Here we report an efficient solution-phase synthetic strategy to obtain two broad families of sugar-oligoamides. The first type, structure vector A (-Py[Me]-γ-Py-Ind), has a methyl group present as a substituent on the nitrogen of pyrrole B, connected to the C terminal of the oligoamide fragment. The second type, structure vector B (-Py[(CH(2))(11)OH]-γ-Py-Ind), has an alkyl chain present on the nitrogen of pyrrole B connected to the C terminal of the oligoamide fragment and has been designed to access to di- and multivalent sugar-oligoamides. By using sequential DIPC/HOBt coupling reactions, the oligoamide fragment -Py[R]-γ-Py-Ind has been constructed. The last coupling reaction between the anomeric amino sugar and the oligoamide fragment was carried out by activating the acid derivative as a BtO- ester, which has been performed by using TFFH. The isolated esters (BtO-Py[R]-γ-Py-Ind) were coupled with selected amino sugars using DIEA in DMF. The synthesis of two different selective model vectors (vector A (1) and vector B (2)) and two types of water-soluble sugar-oligoamide ligands, with vector A structure (compounds 3-7) and with vector B structure (compound 8), was carried out.
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http://dx.doi.org/10.1021/jo302238uDOI Listing
December 2012

Forming spirocyclohexadienone-oxocarbenium cation species in the biomimetic synthesis of amomols.

J Org Chem 2011 Mar 21;76(5):1409-17. Epub 2011 Jan 21.

Département de Pharmacochimie Moléculaire, Université Joseph Fourier-Grenoble 1, CNRS UMR 5063, CNRS ICMG FR 2607, bâtiment André Rassat, 470 rue de la Chimie, F-38041 Grenoble Cedex 9, France.

The oxidation of appropriate 2-(4-hydroxyphenyl)ethyl ketones gives direct access to amomols by means of the formation of a transient spirocyclohexadienone-oxocarbenium ion that is intermolecularly intercepted by an alcohol. Furthermore, homochiral amomols and other new analogues were synthesized for the first time and were biologically evaluated on Plasmodium falciparum.
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http://dx.doi.org/10.1021/jo102414sDOI Listing
March 2011

1-Azaaurones derived from the naturally occurring aurones as potential antimalarial drugs.

Bioorg Med Chem 2010 Aug 9;18(15):5724-31. Epub 2010 Jun 9.

Département de Pharmacochimie Moléculaire, Université de Grenoble I/CNRS, UMR 5063, 470 rue de la Chimie, BP 53 F-38041, Grenoble Cedex 9, France.

We report the synthesis and in vitro antiplasmodial activity of 35 compounds, designed as analogues of the naturally occurring aurones. Several of these analogues showed submicromolar antimalarial activity against a chloroquine-resistant strain of Plasmodium falciparum (FcB1-Columbia strain) cultured on human erythrocytes. Substitution of the intracyclic oxygen in aurones by a nitrogen atom and systematic variation of the substituent at the B-ring revealed promising leads showing good activity on the CQ-resistant strain. In particular, 4,6-dimethoxy-4'-ethylazaaurone 22 showed antiplasmodial potency without noticeable toxicity. The easy synthesis of this family of compounds and the relevant antiplasmodial activity are in favor of promising candidates for further development.
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http://dx.doi.org/10.1016/j.bmc.2010.06.008DOI Listing
August 2010

A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models.

BMC Cancer 2009 Jul 20;9:242. Epub 2009 Jul 20.

Bâtiment Jean Roget, Faculté de Médecine, Grenoble, F-38700 France.

Background: Over the past decades, in spite of intensive search, no significant increase in the survival of patients with glioblastoma has been obtained. The role of the blood-brain barrier (BBB) and especially the activity of efflux pumps belonging to the ATP Binding Cassette (ABC) family may, in part, explain this defect.

Methods: The in-vitro activities of JAI-51 on cell proliferation were assessed by various experimental approaches in four human and a murine glioblastoma cell lines. Using drug exclusion assays and flow-cytometry, potential inhibitory effects of JAI-51 on P-gp and BCRP were evaluated in sensitive or resistant cell lines. JAI-51 activity on in-vitro microtubule polymerization was assessed by tubulin polymerization assay and direct binding measurements by analytical ultracentrifugation. Finally, a model of C57BL/6 mice bearing subcutaneous GL26 glioblastoma xenografts was used to assess the activity of the title compound in vivo. An HPLC method was designed to detect JAI-51 in the brain and other target organs of the treated animals, as well as in the tumours.

Results: In the four human and the murine glioblastoma cell lines tested, 10 muM JAI-51 inhibited proliferation and blocked cells in the M phase of the cell cycle, via its activity as a microtubule depolymerising agent. This ligand binds to tubulin with an association constant of 2 x 105 M-1, overlapping the colchicine binding site. JAI-51 also inhibited the activity of P-gp and BCRP, without being a substrate of these efflux pumps. These in vitro studies were reinforced by our in vivo investigations of C57BL/6 mice bearing GL26 glioblastoma xenografts, in which JAI-51 induced a delay in tumour onset and a tumour growth inhibition, following intraperitoneal administration of 96 mg/kg once a week. In accordance with these results, JAI-51 was detected by HPLC in the tumours of the treated animals. Moreover, JAI-51 was detected in the brain, showing that the molecule is also able to cross the BBB.

Conclusion: These in vitro and in vivo data suggest that JAI-51 could be a good candidate for a new treatment of tumours of the CNS. Further investigations are in progress to associate the title compound chemotherapy to radiotherapy in a rat model.
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http://dx.doi.org/10.1186/1471-2407-9-242DOI Listing
July 2009

Sugar-oligoamides: bound-state conformation and DNA minor-groove-binding description by TR-NOESY and differential-frequency saturation-transfer-difference experiments.

Chemistry 2008 ;14(8):2435-42

Departamento de Química Orgánica Biológica, Instituto de Química Orgánica general, CSIC c/Juan de la Cierva 3, 28006 Madrid, Spain.

Selective-frequency saturation-transfer-difference (STD) spectra allow the description of complexes established between minor-groove binders and long tracts of calf thymus DNA (ct-DNA). Two sets of experiments with selective saturation of either the H1' or H4'/H5'/H5'' proton NMR regions of deoxyribose allow the description of the ligand residues close to the inner (H1') and outer regions (H4'/H5'/H5'') of the minor groove of double-helical DNA. A series of complexes of sugar-oligoamides (2-6) with ct-DNA have been studied by both TR-NOESY and STD experiments. The binding mode of the complexes is similar to that of netropsin (1) and allows us to define a general binding mode for this family of ligands, in which an NH rim points towards the internal area (inner region) and a CH3 rim points towards the external part (outer region) of the minor groove of DNA. Also by means of both TR-NOESY and STD experiments, a description of the asymmetric centers of the sugar residue close to the inner and outer regions of the groove has been achieved. These results confirm that the sugar is responsible for the differences previously found in binding energetics.
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http://dx.doi.org/10.1002/chem.200701103DOI Listing
May 2008

Isolation and antimalarial activity of alkaloids from Pseudoxandra cuspidata.

Planta Med 2006 Aug 10;72(10):894-8. Epub 2006 Aug 10.

Laboratoire Pharmacochimie des Substances Naturelles et Pharmacophores Redox, UMR 152 IRD, Université Toulouse 3 Paul Sabatier, Faculté des Sciences Pharmaceutiques, Toulouse, France.

A novel and very unusual azaanthracene alkaloid, 1-aza-7,8,9,10-tetramethoxy-4-methyl-2-oxo-1,2-dihydroanthracene ( 1) and a new diastereoisomer of the bis-benzylisoquinoline alkaloid rodiasine, 1 S,1' R-rodiasine ( 2), as well as the alkaloids O-methylpunjabine ( 3) and O-methylmoschatoline ( 4) have been isolated from Pseudoxandra cuspidata bark, used in French Guiana as an antimalarial. Their structures were elucidated by spectroscopic analyses, especially 2D-NMR techniques (ADEQUATE and NOESY). We found that the antimalarial activity of this bark was mostly due to bis-benzylisoquinoline 1 S,1' R-rodiasine ( 2) (IC (50)= 1 microM) also displaying a low cytotoxicity.
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http://dx.doi.org/10.1055/s-2006-947184DOI Listing
August 2006

Carbohydrate-based DNA ligands: sugar-oligoamides as a tool to study carbohydrate-nucleic acid interactions.

J Am Chem Soc 2005 Jul;127(26):9518-33

Instituto de Química Orgánica, CSIC, c/ Juan de la Cierva 3, Madrid 28006, Spain.

Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydrate-DNA interactions. The general design of the ligands 1-3 has been done as to favor the bound conformation of Distamycin-type gamma-linked covalent dimers which is a hairpin conformation. Indeed, NMR analysis of the sugar-oligoamides in the free state has indicated the presence of a percentage of a hairpin conformation in aqueous solution. The DNA binding activity of compounds 1-3 was confirmed by calf thymus DNA (ct-DNA) NMR titration. Interestingly, the binding of the different sugar-oligoamides seems to be modulated by the sugar configuration. Semiquantitative structural information about the DNA ligand complexes has been derived from NMR data. A competition experiment with Netropsin suggested that the sugar-oligoamide 3 bind to DNA in the minor groove. The NMR titrations of 1-3 with poly(dA-dT) and poly(dG-dC) suggested preferential binding to the ATAT sequence. TR-NOE NMR experiments for the sugar-oligoamide 3-ct-DNA complex both in D(2)O and H(2)O have confirmed the complex formation and given information on the conformation of the ligand in the bound state. The data confirmed that the sugar-oligoamide ligand is a hairpin in the bound state. Even more relevant to our goal, structural information on the conformation around the N-glycosidic linkage has been accessed. Thus, the sugar asymmetric centers pointing to the NH-amide and N-methyl rims of the molecule have been characterized.
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http://dx.doi.org/10.1021/ja050794nDOI Listing
July 2005

N-acyl substituted 7-amino-4-chloroisocoumarin: a peptide degradation model via an imide mechanism.

Bioorg Med Chem Lett 2004 Apr;14(7):1771-4

INSERM U-382, Institut de Biologie du Développement de Marseille, CNRS-INSERM-Université de la Méditerranée, Faculté des Sciences de Luminy, case 907, 13288 Marseille Cedex 09, France.

During the coupling reaction between 3-alkoxy-7-amino-4-chloroisocoumarin and N-acyl alanine dipeptide, an unexpected deamidation reaction was observed. The proposed mechanism for this reaction involved the formation of an imide intermediate which after cleavage led to the release of amino acid moiety. The described deamidation reaction represents the first chemical model involving a non-peptidic moiety, which mimics biological and chemical deamidation processes occurring in proteins or peptides incorporating an asparagine or a glutamine residue.
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http://dx.doi.org/10.1016/j.bmcl.2004.01.030DOI Listing
April 2004

New antiviral nucleoside prodrugs await application.

Curr Med Chem 2003 Sep;10(18):1825-43

Laboratoire de Chimie Biomoléculaire, INSERM U382, Institut de Biologie du Développement de Marseille, Université de la Méditerranée, Parc Scientifique de Luminy, 163 avenue de Luminy, case 901, 13288 Marseille cedex 9, France.

In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome some drug deficiencies. Examples of antiviral carrier-linked nucleoside prodrugs or nucleoside bioprecursors are described, and their active mechanisms discussed. The described nucleoside prodrugs are classified in two structural classes: prodrugs bearing molecular modifications on the sugar moiety and prodrugs bearing molecular modifications on the nucleic base. Despite the important research work accomplished through out the world during the last few years in developing improved antiviral drugs for the treatment of HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HSV (herpes simplex virus), HCMV (human cytomegalovirus), etc infections, only few nucleoside antiviral prodrugs are marketed, while promising prodrugs deriving from original concepts were developed. The most relevant concepts are discussed: (1) - pronucleotide approach allows the design of prodrugs, which by-pass the first kinase phosphorylation step; (2) - drug design based on Bodor's concept for brain delivery improved drugs and (3) - 5'-O-carbonate nucleosides and deaminase approaches, which allow active drug regeneration. Nonetheless, none of these innovative models have reached the market.
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http://dx.doi.org/10.2174/0929867033457034DOI Listing
September 2003
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