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1. Theionbrunonines A and B: Dimeric Vobasine Alkaloids Tethered by a Thioether Bridge from Mostuea brunonis

Author

Philippe Grellier, Elvis Otogo N’Nang, Pierre Champy, Mehdi A. Beniddir, Brice Kumulungui, Guillaume Bernadat, Erwan Poupon, Elisabeth Mouray, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire de chimie et biochimie des substances naturelles, Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Centre International de Recherches Médicales de Franceville (CIRMF), Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pharmacognosie (BioCIS), Muséum national d'Histoire naturelle (MNHN), and UFR Pharmacie, Laboratoire de Pharmacognosie, BioCIS

Subjects
0301 basic medicine, Stereochemistry, Monoterpene, [SDV]Life Sciences [q-bio], [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Thioether, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, ComputingMilieux_MISCELLANEOUS, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, Plasmodium falciparum, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, biology.organism_classification, Mostuea brunonis, 3. Good health, 0104 chemical sciences, 030104 developmental biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Molecular networking
Abstract

Theionbrunonines A and B (1 and 2), the first examples of monoterpene bisindole alkaloids linked by a thioether bridge, were isolated from the stems of Mostuea brunonis, guided by a molecular networking-based dereplication strategy. Their structures were elucidated by a combination of spectroscopic data and ECD calculations. A plausible biosynthetic pathway for 1 and 2 was postulated. Theionbrunonines A and B (1 and 2) showed moderate antiplasmodial activities in the micromolar range against the strain FcB1 of Plasmodium falciparum and no cytotoxic activity against the MRC-5 cell line at 20 μM.

Published
2018

2. Corynanthean-Epicatechin Flavoalkaloids from Corynanthe pachyceras

Author

Kouamé, Tapé, Okpekon, Aboua Timothée, Bony, Nicaise, N'Tamon, Amon Diane, Gallard, Jean-François, Rharrabti, Somia, Leblanc, Karine, Mouray, Elisabeth, Grellier, Philippe, Champy, Pierre, Beniddir, Mehdi, Le Pogam, Pierre, N’tamon, Amon Diane, Laboratoire de Chimie des Substances Naturelles (LCSN), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Laboratoire de Chimie Organique et de Substances Naturelles (LCOSN), Université Félix Houphouët-Boigny (UFHB), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'océanographie et de biogéochimie (LOB), Université de la Méditerranée - Aix-Marseille 2-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)

Subjects
Magnetic Resonance Spectroscopy, Monoterpene, [SDV]Life Sciences [q-bio], Flavonoid, Pharmaceutical Science, Corynanthean, Corynanthe pachyceras, 01 natural sciences, Catechin, Mass Spectrometry, Indole Alkaloids, Analytical Chemistry, Pausinystalia, Drug Discovery, MESH: Pausinystalia, ComputingMilieux_MISCELLANEOUS, rubiaceae, MESH: Inhibitory Concentration 50, Anthelmintics, chemistry.chemical_classification, 0303 health sciences, molecular networking, MESH: Plant Stems, Molecular Structure, Plant Stems, Chemistry, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Anthelmintics, Chemistry (miscellaneous), Molecular networking, Plant Bark, Molecular Medicine, MESH: Monoterpenes, Two-dimensional nuclear magnetic resonance spectroscopy, MESH: Plant Bark, Stereochemistry, MESH: Catechin, MESH: Molecular Structure, Article, lcsh:QD241-441, Inhibitory Concentration 50, 03 medical and health sciences, lcsh:Organic chemistry, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, 030304 developmental biology, Flavonoids, monoterpene indole alkaloids, MESH: Mass Spectrometry, Stem bark, Indole alkaloid, 010405 organic chemistry, MESH: Magnetic Resonance Spectroscopy, Organic Chemistry, 0104 chemical sciences, MESH: Indole Alkaloids, flavoalkaloids, Monoterpenes, MESH: Flavonoids
Abstract

International audience; Epicatechocorynantheines A and B, and epicatechocorynantheidine were isolated from the stem bark of Corynanthe pachyceras. These molecules were pinpointed, and their isolation streamlined, by a molecular networking strategy. The structural elucidation was unambiguously accomplished from HRMS and 1D/2D NMR data. These compounds represent the first examples of corynanthean-type alkaloids tethered with a flavonoid. Epicatechocorynantheidine notably instigated two connections between the monoterpene indole alkaloid and the flavonoid, yielding an unprecedented octacyclic appendage. These flavoalkaloids exerted moderate antiplasmodial activities.

Published
2020
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3. Palladium(II)-Catalyzed Diastereoselective 2,3-Trans C(sp3)–H Arylation of Glycosides

Author

Samir Messaoudi, Nicolas Probst, Mouâd Alami, Vincent Gandon, Slimane Dahaoui, Gwendal Grelier, Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Cristallographie, Résonance Magnétique et Modélisations (CRM2), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire de chimie moléculaire (LCM), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)

Subjects
chemistry.chemical_classification, C glycosides, 010405 organic chemistry, Aryl, chemistry.chemical_element, Glycoside, General Chemistry, 010402 general chemistry, 01 natural sciences, Medicinal chemistry, Catalysis, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Stereoselectivity, [CHIM.OTHE]Chemical Sciences/Other, ComputingMilieux_MISCELLANEOUS, Palladium
Abstract

We report herein the diastereoselective C(sp3)–H arylation of glycosides. A wide range of β- and α-glycosides proved able to selectively undergo Pd(II)-catalyzed coupling with diverse aryl iodides to assemble a large library of functionalized 3-arylglycosylamides. DFT calculations were performed to elucidate the unexpected trans stereoselectivity of this reaction.

Published
2018
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4. Brazilian red propolis: Chemical composition and antibacterial activity determined using bioguided fractionation

Author

Françoise Dumas, Mariana Roesch-Ely, Charlene Silvestrin Celi Garcia, Christine Thomassigny, Sylvie Bouttier, João Antonio Pêgas Henriques, Paola Luchtenberg, Luciane Corbellini Rufatto, Sidnei Moura, University of Caxias do Sul, Caxias do Sul (UCS), Institut Lavoisier de Versailles (ILV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Biomolécules : Conception, Isolement, Synthèse (BioCIS), and Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY)

Subjects
0301 basic medicine, Cell Survival, Context (language use), Microbial Sensitivity Tests, Biology, Chemical Fractionation, 01 natural sciences, Microbiology, High-performance liquid chromatography, Mass Spectrometry, Propolis, Biochanin A, 03 medical and health sciences, chemistry.chemical_compound, Chlorocebus aethiops, Formononetin, Animals, [CHIM]Chemical Sciences, Vero Cells, Chromatography, High Pressure Liquid, ComputingMilieux_MISCELLANEOUS, Biological Products, Chromatography, Bacteria, 010401 analytical chemistry, Epithelial Cells, 0104 chemical sciences, Anti-Bacterial Agents, 030104 developmental biology, chemistry, Gas chromatography, Liquiritigenin, Antibacterial activity, Brazil
Abstract

The indiscriminate use of antibiotics is causing an increase in bacterial resistance, complicating therapeutic planning. In this context, natural products have emerged as major providers of bioactive compounds. This work performs a bioguided study of Brazilian red propolis to identify compounds with antibacterial potential and to evaluate their cytotoxicity against non-tumour cells. Using bioguided fractionation performed with the hydroalcoholic extract of red propolis from Alagoas, it was possible to obtain subfractions with remarkable bacteriostatic activity compared with the precursor fractions. The SC2 subfraction was highlighted and showed the best results with minimal inhibitory concentrations (MICs) of 56.75, 28.37, 454.00, and 227.00 μg mL-1 against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa, respectively. However, this study also revealed a cytotoxic effect against the non-tumour Vero cell line. Furthermore, through chemical analyses using high resolution mass spectrometry, high performance liquid chromatography with UV detection, and gas chromatography coupled to mass spectrometry, we verified the presence of important marker compounds in the fractions and extracts, including formononetin (m/z 267.0663), biochanin A (m/z 283.0601), and liquiritigenin (m/z 255.0655). The results obtained in this study suggest an important antibacterial potential of red propolis subfractions. In this context, the bioguided fractionation has been a useful process, due to its ability to isolate and concentrate active compounds in a logical and rational way.

Published
2018
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5. Revisiting Previously Investigated Plants: A Molecular Networking-Based Study of Geissospermum laeve

Author

Jean-François Gallard, Philippe M. Loiseau, Sébastien Pomel, Alexander E. Fox Ramos, Laurent Evanno, Erwan Poupon, Elisabeth Mouray, Christophe Duplais, Jean-Christophe Jullian, Marc Litaudon, Philippe Grellier, Alexandre Maciuk, Mehdi A. Beniddir, Charlotte Fox Alcover, Guillaume Bernadat, Pierre Champy, Équipe 'Pharmacognosie-Chimie des Substances Naturelles' BioCIS, Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Ecologie des forêts de Guyane (UMR ECOFOG), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-AgroParisTech-Université de Guyane (UG)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Biochimie des Substances Naturelles, Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Laboratoire de Pharmacognosie (BioCIS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université des Antilles (UA)-Université de Guyane (UG)-Centre National de la Recherche Scientifique (CNRS)-AgroParisTech-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA), Laboratoire de chimie et biochimie des substances naturelles, Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cienciactiva, an initiative of the National Council for Science, Technology and Technological Innovation (CONCYTEC) [239-2015-FONDECYT], French ANR [ANR-15-CE29-0001], Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, food.ingredient, Stereochemistry, Antiparasitic, medicine.drug_class, Monoterpene, Plasmodium falciparum, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Analytical Chemistry, Indole Alkaloids, 03 medical and health sciences, Antimalarials, food, Parasitic Sensitivity Tests, Drug Discovery, Secologanin Tryptamine Alkaloids, medicine, Organic chemistry, Humans, Nuclear Magnetic Resonance, Biomolecular, ComputingMilieux_MISCELLANEOUS, Pharmacology, Indole test, Apocynaceae, biology, Antiparasitic Agents, Molecular Structure, 010405 organic chemistry, Geissospermum, Organic Chemistry, Absolute configuration, biology.organism_classification, Antiparasitic agent, 0104 chemical sciences, French Guiana, Plant Leaves, 030104 developmental biology, Complementary and alternative medicine, Molecular Medicine, Drug Screening Assays, Antitumor, Leishmania donovani
Abstract

International audience; Three new monoterpene indole alkaloids (13) have been isolated from the bark of Geissospermum laeve-, together with the known alkaloids (-)-leuconolam (4), geissolosimine (5), and geissospermine (6). The structures of 1-3 were elucidated by analysis of their HRMS and NMR spectroscopic data. The absolute configuration of geissolaevine (I). was deduced from the comparison of experimental and theoretically calculated ECD spectra. The isolation workflow was guided by a molecular networking-based dereplication strategy using an in-house database of monoterpene indole alkaloids. In addition, five known compounds previously undescribed in the Geissospermum genus were dereplicated from the G. laeve alkaloid extract network and were assigned with various levels of identification confidence. The antiparasitic activities against Plasmodium falciparum and Leishmania donovani as well as the Ortotoxic activity against the MRC-5 cell line were determined for compounds 1-5.

Published
2017
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6. The Marine Guanidine Alkaloid Crambescidin 816 Induces Calcium Influx and Cytotoxicity in Primary Cultures of Cortical Neurons through Glutamate Receptors

Author

Carmen Vale, Luis M. Botana, Aida G. Mendez, Víctor Martín Vázquez, Amparo Alfonso, Olivier P. Thomas, Andrea Boente Juncal, Mercedes R. Vieytes, Siguara B. L. Silva, Departamento de Farmacologia Facultad de Veterianaria, Universidad de Santiago de Compostela [Spain] (USC), UFR Pharmacie, Laboratoire de Pharmacognosie, BioCIS, Géoazur (GEOAZUR 7329), Université Côte d'Azur (UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), National University of Ireland [Galway] (NUI Galway), Departamento de Fisiología, Facultad de Veterinaria, Department of Pharmacology, Universidade de Santiago de Compostela, Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Universidade de Santiago de Compostela [Spain] (USC ), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])

Subjects
0301 basic medicine, Patch-Clamp Techniques, Physiology, Biochemistry, Mice, 0302 clinical medicine, Cytosol, Cytotoxicity, Cells, Cultured, Cellular Senescence, Cerebral Cortex, Neurons, Voltage-dependent calcium channel, Molecular Structure, Miniature Postsynaptic Potentials, Glutamate receptor, General Medicine, Calcium Channel Blockers, Cell biology, Receptors, Glutamate, glutamate receptors, cytotoxicity, crambescidin 816, cytosolic Ca 2+, Nifedipine, Cations, Divalent, Cell Survival, Cognitive Neuroscience, chemistry.chemical_element, [SDU.STU]Sciences of the Universe [physics]/Earth Sciences, Biology, Calcium, 03 medical and health sciences, Alkaloids, Extracellular, Animals, Spiro Compounds, Patch clamp, Dose-Response Relationship, Drug, cortical neurons, T-type calcium channel, Excitatory Postsynaptic Potentials, Cell Biology, 030104 developmental biology, chemistry, Excitatory Amino Acid Antagonists, Guanidine alkaloids, 030217 neurology & neurosurgery
Abstract

International audience; Crambescidin 816 is a guanidine alkaloid produced by the sponge Crambe crambe with known antitumoral activity. While the information describing the effects of this alkaloid in central neurons is scarce, Cramb816 is known to block voltage dependent calcium channels being selective for L-type channels. Moreover, Cramb816 reduced neuronal viability through an unknown mechanism. Here, we aimed to describe the toxic activity of Cramb816 in cortical neurons. Since calcium influx is considered the main mechanism responsible for neuronal cell death, the effects of Cramb816 in the cytosolic calcium concentration of cortical neurons were studied. The alkaloid decreased neuronal viability and induced a dose-dependent increase in cytosolic calcium that was also related to the presence of calcium in the extracellular media. The increase in calcium influx was age dependent, being higher in younger neurons. Moreover, this effect was prevented by glutamate receptor antagonists, which did not fully block the cytotoxic effect of Cramb816 after 24 h of treatment but completely prevented Cramb816 cytotoxicity after 10 min exposure. Therefore, the findings presented herein provide new insights into the cytotoxic effect of Cramb816 in cortical neurons.

Published
2017
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7. Identification of the Environmental Neurotoxins Annonaceous Acetogenins in an Annona cherimolia Mill. Alcoholic Beverage Using HPLC-ESI-LTQ-Orbitrap

Author

Alain Brunelle, David Touboul, Jessica Le Ven, Guy Lewin, Pierre Champy, Isabelle Schmitz-Afonso, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire de Pharmacognosie (BioCIS), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Acetogenins, Neurotoxins, Annonacin, Food Contamination, Biology, Orbitrap, High-performance liquid chromatography, Annona, law.invention, chemistry.chemical_compound, law, Botany, Annona cherimolia, Chromatography, High Pressure Liquid, Traditional medicine, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Alcoholic Beverages, General Chemistry, biology.organism_classification, 3. Good health, chemistry, Annonaceae, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Atypical Parkinsonism, Annonaceous Acetogenins, General Agricultural and Biological Sciences
Abstract

International audience; Epidemiological and toxicological studies have suggested Annonaceaeous acetogenins to be environmental neurotoxins responsible for sporadic atypical parkinsonism/dementia in tropical areas. These compounds are present in the tropical genus Annona (Annonaceae), known for its fruit-yielding cultivated species such as Annona cherimolia. This species is widely cultivated in South America, Spain, and Portugal and yields acetogenins in its seeds, stems, and roots. The presence of these compounds in the pulp of its fruit and in derived food products is unclear. An innovative and sensitive methodology by HPLC-ESI-LTQ-Orbitrap with postcolumn infusion of lithium iodide was used to identify the presence of low levels of acetogenins in an A. cherimolia Mill. fruit-based commercial alcoholic beverage. More than 80 representatives were detected, and the 31 most intense acetogenins were identified. All together these findings indicate that this species should be considered as a risk factor within the framework of a worldwide problem of food toxicity.

Published
2014
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8. Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice

Author

Wolfgang H. Oertel, Bertrand Friguet, Gesine Respondek, Günter U. Höglinger, Matthias Höllerhage, Agathe Tarze, Stefanie Müssner, Mohamed Salama, Christel Depienne, Agnès Rastetter, Anderson de Andrade, Pierre Champy, Elizabeth Sumi Yamada, Guellaen, Georges, Experimental Neurology, Philipps University, Experimental Neuropathology Laboratory, University Hospital João de Barros Barreto-Federal University of Para - Universidade Federal do Pará - UFPA [Belém, Brazil] (UFPA), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Department of Neurology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biologie Cellulaire du vieillissement, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR83, Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Deutsche Forschungsgemeinschaft (HO2402/6-1, HO2402/8-1), the German Ministry of Education and Research (BMBF EF 10-54), the Centre National de la Recherche Scientifique (CNRS), a Marie Curie Incoming International Fellowship (21996 to E.S.Y.) and the German Academic Exchange Service (DAAD to A.C.F.d.A.)., University Hospital João de Barros Barreto-Federal University of Para - Universidade Federal do Para [Belem - Brésil], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Intégrative (IFR-BI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Neurons, pharmacology [Enzyme Inhibitors], drug effects [Gene Expression Regulation], genetics [Gene Expression Regulation], drug effects [Microglia], MESH: Dose-Response Relationship, Drug, Mice, Lactones, chemistry.chemical_compound, 0302 clinical medicine, MESH: Animals, Phosphorylation, pharmacology [Furans], Enzyme Inhibitors, genetics [Arginine], Neurons, 0303 health sciences, Kinase, Neurodegeneration, neurodegeneration, MESH: Arginine, Tryptophan, Brain, MESH: Gene Expression Regulation, Mitochondria, MESH: tau Proteins, Cell biology, MESH: Microglia, Neurology, Biochemistry, MESH: Enzyme Inhibitors, drug effects [Brain], Microglia, genetics [Tryptophan], Tauopathy, Microtubule-Associated Proteins, MESH: Lactones, Genetically modified mouse, MESH: Mutation, MESH: Mice, Transgenic, MESH: Mitochondria, Annonacin, Mice, Transgenic, genetics [Mutation], MAPT protein, human, tau Proteins, Biology, Arginine, MESH: Brain, 03 medical and health sciences, drug effects [Phosphorylation], Developmental Neuroscience, MESH: Mice, Inbred C57BL, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, drug effects [Neurons], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ddc:610, Mortality, genetics [Phosphorylation], Furans, MESH: Mice, MESH: Tryptophan, 030304 developmental biology, MESH: Humans, MESH: Mortality, MESH: Phosphorylation, Dose-Response Relationship, Drug, Cyclin-dependent kinase 5, tauopathy, MESH: Furans, metabolism [Microtubule-Associated Proteins], annonacin, metabolism [Mitochondria], medicine.disease, Mice, Inbred C57BL, MESH: Microtubule-Associated Proteins, genetics [tau Proteins], Somatodendritic compartment, Gene Expression Regulation, chemistry, environmental neurotoxin, metabolism [Brain], Mutation, pharmacology [Lactones], genetics [Mitochondria], microtubule-associated protein tau, 030217 neurology & neurosurgery
Abstract

International audience; Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.

Published
2014
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9. The fruit of Annona squamosa L. as a source of environmental neurotoxins: From quantification of squamocin to annotation of Annonaceous acetogenins by LC–MS/MS analysis

Author

Idensi Bajin ba Ndob, Natacha Bonneau, François Senejoux, Lamia Baloul, Pierre Champy, Institut de Médecine Traditionnelle Chinoise (IMTC), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), UFR Pharmacie, Laboratoire de Pharmacognosie, BioCIS, Centre National de la Recherche Scientifique (CNRS), Unité de Nutrition Humaine - Clermont Auvergne (UNH), and Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA)

Subjects
annona squamosa, Acetogenins, mass spectrum analysis, maladie de parkinson, 01 natural sciences, Annona, Analytical Chemistry, chemistry.chemical_compound, Lactones, 0302 clinical medicine, Tandem Mass Spectrometry, spectrométrie de masse, polycyclic compounds, squamocin, Chromatography, High Pressure Liquid, Traditional medicine, biology, General Medicine, pathophysiologie, female genital diseases and pregnancy complications, atypical parkinsonism, Caribbean Region, Annonaceae, annona squamosa L, primary Parkinsonism, Bullatacin, HPLC–MS/MS, Asia, bullatacin, Neurotoxins, Annonacin, neurotoxine, 03 medical and health sciences, Qualitative analysis, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, analyse qualitative, Lc ms ms, qualitative analysis, liquid chromatography, Furans, 010401 analytical chemistry, Annona squamosa, neurotoxin, annonacin, biology.organism_classification, 0104 chemical sciences, chemistry, Fruit, chromatographie liquide, Atypical Parkinsonism, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, annonaceous acetogenins, Annonaceous Acetogenins, désordre neurodégénératif, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Food Science
Abstract

The authors are grateful to Dr David Touboul, Isabelle-Schmitz-Afonso (ICSN-CNRS), Dr Marie Mejean and Marine Leblanc for fruitful discussions and guidance, and to Estella Vallade for technical assistance. Natacha Bonneau is the recipient of a doctoral grant from the Ministere de l'enseignement superieur et de la recherche (France); Annonaceous acetogenins (AAGs) are neurotoxins possibly responsible for atypical Parkinsonism/dementiaclusters, via the consumption of edible Annonaceae fruits. Their presence was investigated in fruitpulps of Annona squamosa from different locations. Qualitative analysis of other AAGs was performed.We here report the identification of squamocin in batches from Asia, the Caribbean Basin and theIndian Ocean. This molecule was quantified by HPLC-UV, evidencing a content of 13.5–36.4 mg/fruit.HPLC-ESI-Q-TOF allowed the detection of 25 different raw formulas matching with AAGs. LC–MS/MSmethodological development was performed using 4 representative standards. The main AAGs couldbe annotated, including bullatacin (rolliniastatin-2) and annonacin. This study evidences a remarkablehomogeneity for the main AAGs within the species, and discrepancies for minor compounds. These findingsindicate that A. squamosa should be considered a risk factor for neurodegenerative disorders

Published
2017
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10. Pleiokomenines A and B: Dimeric Aspidofractinine Alkaloids Tethered with a Methylene Group

Author

Erwan Poupon, Laurent Evanno, Brice Kumulungui, Jean-François Gallard, Mehdi A. Beniddir, Elisabeth Mouray, Grégory Genta-Jouve, Elvis Otogo N’Nang Obiang, Pierre Champy, Philippe Grellier, Grellier, Philippe, Université de Picardie Jules Verne (UPJV), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre International de Recherches Médicales de Franceville (CIRMF), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Muséum national d'Histoire naturelle (MNHN), Équipe 'Pharmacognosie-Chimie des Substances Naturelles' BioCIS, Centre National de la Recherche Scientifique (CNRS), Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), UFR Pharmacie, Laboratoire de Pharmacognosie, BioCIS, Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherches Médicales de Franceville, and Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Stereochemistry, [SDV]Life Sciences [q-bio], [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Formaldehyde, Aspidofractinine, chemistry.chemical_element, Methylene bridge, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Biochemistry, Pleiocarpa mutica, chemistry.chemical_compound, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Scandium, Physical and Theoretical Chemistry, Methylene, Derivatization, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, ComputingMilieux_MISCELLANEOUS, [SDV.BV.PEP] Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, biology, 010405 organic chemistry, Organic Chemistry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, biology.organism_classification, 0104 chemical sciences, 3. Good health, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Trifluoromethanesulfonate, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

Pleiokomenines A and B (1 and 2), first examples of dimeric aspidofractinine alkaloids linked by a methylene bridge, were isolated from the stem bark of Pleiocarpa mutica. Their structures were elucidated by a combination of spectroscopic analyses and semisynthetic derivatization of pleiocarpinine (3) and a formaldehyde equivalent mediated by scandium trifluoromethanesulfonate. Pleiokomenines A (1) and B (2) showed moderate antiplasmodial activities in the micromolar range against the FcB1 strain.

Published
2017

11. Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model

Author

María Roel, Luis M. Botana, Laura Sánchez, Rafael López, Juan A. Rubiolo, Pablo Cabezas-Sainz, Olivier P. Thomas, Siguara B. L. Silva, Jorge Guerra-Varela, Department of Pharmacology, Universidade de Santiago de Compostela, Department Farmacologia, University of Santiago de Compostela, Departamento de Genética, Universidad de Santiago de Compostela [Spain] (USC), Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), School of Chemistry, Marine Biodiscovery, National University of Ireland Galway, Géoazur (GEOAZUR 7329), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Translational Medical Oncology, Health Research Institute of Santiago, Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica, Universidade de Santiago de Compostela. Departamento de Zooloxía, Xenética e Antropoloxía Física, Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])

Subjects
0301 basic medicine, Time Factors, Colorectal cancer, Cell, Apoptosis, Cell Cycle Proteins, p53-mediated g(1) arrest, 0302 clinical medicine, anoikis, Zebrafish, Cytoskeleton, Cyclin, Membrane Potential, Mitochondrial, zebrafish xenograft model, biology, Kinase, Caspase 3, Hep G2 Cells, 3. Good health, Cancer treatment, Tumor Burden, mitochondria, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, MCF-7 Cells, Colorectal Neoplasms, HT29 Cells, Research Paper, Signal Transduction, Cell Cycle Inhibition, Cell Survival, [SDU.STU]Sciences of the Universe [physics]/Earth Sciences, Antineoplastic Agents, cancer treatment, 03 medical and health sciences, Inhibitory Concentration 50, crambescidins, Alkaloids, medicine, Cell Adhesion, Animals, Humans, Spiro Compounds, sponge crambe-crambe, cell cycle inhibition, Guanidine, Cell Proliferation, Dose-Response Relationship, Drug, pathway, human cancer, medicine.disease, biology.organism_classification, G1 Phase Cell Cycle Checkpoints, Xenograft Model Antitumor Assays, 030104 developmental biology, Cancer research, cells, cyclin-dependent kinases, progression
Abstract

// Maria Roel 1 , Juan A. Rubiolo 1 , Jorge Guerra-Varela 2 , Siguara B. L. Silva 3, 4 , Olivier P. Thomas 3, 5 , Pablo Cabezas-Sainz 2 , Laura Sanchez 2 , Rafael Lopez 6 , Luis M. Botana 1 1 Department of Pharmacology, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain 2 Department of Genetics, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain 3 Geoazur, UMR Universite Nice Sophia Antipolis-CNRS-IRD-OCA, 06560 Valbonne, France 4 Laboratoire de Pharmacognosie, UMR CNRS 8076 BioCIS, LabEx LERMIT, Universite Paris-Sud, Faculte de Pharmacie, 92290 Châtenay-Malabry, France 5 School of Chemistry, Marine Biodiscovery, National University of Ireland Galway, SW4 Galway, Ireland 6 Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain Correspondence to: Luis M. Botana, email: luis.botana@usc.es Keywords: crambescidins, cell cycle inhibition, apoptosis, zebrafish xenograft model, cancer treatment Received: March 13, 2016 Accepted: September 27, 2016 Published: November 04, 2016 ABSTRACT The marine environment constitutes an extraordinary resource for the discovery of new therapeutic agents. In the present manuscript we studied the effect of 3 different sponge derived guanidine alkaloids, crambescidine-816, -830, and -800. We show that these compounds strongly inhibit tumor cell proliferation by down-regulating cyclin-dependent kinases 2/6 and cyclins D/A expression while up-regulating the cell cyclin-dependent kinase inhibitors -2A, -2D and -1A. We also show that these guanidine compounds disrupt tumor cell adhesion and cytoskeletal integrity promoting the activation of the intrinsic apoptotic signaling, resulting in loss of mitochondrial membrane potential and concomitant caspase-3 cleavage and activation. The crambescidin 816 anti-tumor effect was fnally assayed in a zebrafish xenotransplantation model confirming its potent antitumor activity against colorectal carcinoma in vivo . Considering these results crambescidins could represent promising natural anticancer agents and therapeutic tools.

Published
2016
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12. Iron-promoted C-C bond formation in the total synthesis of natural products and drugs

Author

Julien Legros, Bruno Figadère, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pharmacognosie (BioCIS), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Biological Products, Molecular Structure, Chemistry, Iron, Organic Chemistry, education, Total synthesis, chemistry.chemical_element, Bond formation, Biochemistry, Carbon, 3. Good health, Iron salts, Pharmaceutical Preparations, Drug Discovery, Molecule, Organic chemistry, [CHIM]Chemical Sciences, Stoichiometry
Abstract

Covering: up to 2015 Iron salts are inexpensive and almost innocuous; they are thus the promoters of choice, even in stoichiometric amounts, for the formation of carbon–carbon bonds in the backbone of complex molecules. This review encompasses the key role of iron complexes in the total synthesis of some natural products or pharmacologically important compounds.

Published
2015
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13. Solvent systems

Author

Renault, Jean-Hugues, Nuzillard, Jean-Marc, Intes, Olivier, Maciuk, Alexandre, Isolement, structure, transformations et synthèse de substances naturelles (ISTSSN), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), and Alain Berthod

Subjects
[CHIM.ANAL]Chemical Sciences/Analytical chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2005
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14. Anion-Exchange Displacement Centrifugal Partition Chromatography

Author

Jean-Marc Nuzillard, Rodolphe Margraff, Jean-Hugues Renault, Alexandre Maciuk, Philippe Trébuchet, Monique Zèches-Hanrot, Isolement, structure, transformations et synthèse de substances naturelles (ISTSSN), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie des Substances Naturelles (ICMRCSN), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-SFR Condorcet, Agence nationale de la sécurité des systèmes d'information (ANSSI), and Université de Reims Champagne-Ardenne (URCA)

Subjects
Chromatography, Ion exchange, 010405 organic chemistry, Chemistry, Elution, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Hydrophilic interaction chromatography, 010401 analytical chemistry, Ion chromatography, 01 natural sciences, Displacement chromatography, High-performance liquid chromatography, 0104 chemical sciences, Analytical Chemistry, Countercurrent chromatography, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Chromatography column, ComputingMilieux_MISCELLANEOUS, [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract

Ion-exchange displacement chromatography has been adapted to centrifugal partition chromatography. The use of an ionic liquid, benzalkonium chloride, as a strong anion-exchanger has proven to be efficient for the preparative separation of phenolic acid regioisomers. Multigram quantities of a mixture of three hydroxycinnamic acid isomers were separated using iodide as a displacer. The displacement process was characterized by a trapezoidal profile of analyte concentration in the eluate with narrow transition zones. By taking advantage of the partition rules involved in support-free liquid-liquid chromatography, a numerical separation model is proposed as a tool for preliminary process validation and further optimization.

Published
2004
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15. Spectroscopic data of new cassane diterpenoids from the root bark of Erythrophleum suaveolens .

Author

Konan JD, Attioua BK, Kabran FA, Ahmont Kablan CL, Koffi AA, Any-Grah SA, Sissouma D, Seon-Meniel B, LeBlanc K, Jullian JC, Beniddir MA, and Champy P

Abstract

The data are related to the research article entitled ''New cassane diterpenoids from the root bark of Erythrophleum suaveolens'' (Jacques et al., 2019). The article provides method of purification and data to determine structure of two novel cassane diterpenoid amines: 3β-hydroxy-3-methylbutanoyloxy-6α-hydroxy-nor-cassamine (1) and 3β-hydroxy-3-methylbutanoyloxy-erythrosuamine (2). This data in brief provides IR, NMR and Q-TOF-MS spectra, along with fragmentation pathways that allowed to the identification of both new compounds.

Published
2019
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16. Structural Characterisation of Acetogenins from Annona muricata by Supercritical Fluid Chromatography Coupled to High-Resolution Tandem Mass Spectrometry.

Author

Laboureur L, Bonneau N, Champy P, Brunelle A, and Touboul D

Subjects
Chromatography, Liquid methods, Limit of Detection, Sensitivity and Specificity, Time Factors, Acetogenins chemistry, Annona chemistry, Chromatography, Supercritical Fluid methods, Tandem Mass Spectrometry methods
Abstract

Introduction: Acetogenins are plant polyketides known to be cytotoxic and proposed as antitumor candidates. They are also suspected to be alimentary neurotoxins. Their occurrence as complex mixtures renders their dereplication and structural identification difficult using liquid chromatography coupled to tandem mass spectrometry and efforts are required to improve the methodology., Objective: To develop a supercritical fluid chromatography (SFC) high-resolution tandem mass spectrometry method, involving lithium post-column cationisation, for the structural characterisation of Annonaceous acetogenins in crude extracts., Methodology: The seeds of Annona muricata L. were extracted with methanol. Supercritical fluid chromatography of the extract, using a 2-ethylpyridine stationary phase column, was monitored using a high-resolution quadrupole time-of-flight mass spectrometer. Lithium iodide was added post-column in the make-up solvent. For comparison, the same extract was analysed using high-pressure liquid chromatography coupled to the same mass spectrometer, with a column based on solid core particles., Results: Sensitivity was similar for both HPLC and SFC approaches. Retention behaviour and fragmentation pathways of three different isomer groups are described. A previously unknown group of acetogenins was also evidenced for the first time., Conclusion: The use of SFC-MS/MS allows the reduction of the time of analysis, of environmental impact and an increase in the chromatographic resolution, compared to liquid chromatography. This new methodology enlightened a new group of acetogenins, isomers of montanacin-D. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Published
2017
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17. 1 H qNMR Quantification of Annonaceous Acetogenins in Crude Extracts of Annona muricata L. Fruit Pulp.

Author

Bonneau N, Cynober T, Jullian JC, and Champy P

Subjects
Furans analysis, Magnetic Resonance Spectroscopy, Protons, Acetogenins analysis, Annona chemistry, Food Analysis, Fruit chemistry, Plant Extracts analysis
Abstract

Introduction: Annonaceous acetogenins (AAGs) constitute a group of environmental neurotoxins, possibly implicated in sporadic atypical Parkinsonism/dementia complexes. The recent evidencing of complex mixtures of AAGs in edible fruits and derived food products requires efficient and practical analytical tools for an estimation of human exposure., Objective: To develop a simple method for the direct quantitation of the majority of AAGs (sub-types 1a and 1b) within crude extracts, using commonly available 1 H-NMR spectrometers, for food control., Methodology: Method development was carried out on 400 MHz and 300 MHz spectrometers, for routine application on fruits crude extracts of Annona muricata L. The method was validated with annonacin and squamocin as reference compounds. Two internal standards (ISs), fumaric acid and dimethyl fumarate, were successfully used, in deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), respectively., Results: Quantitation was carried out using signals corresponding to the deshielded ethylenic protons characterising most AAGs, at δ 7.18 or δ 6.98 ppm in CDCl 3 . The limit of quantification (LOQ) was 2.5 mM, with acceptable accuracy, and the limit of detection (LOD) was 0.5 mM. The AAGs contents measured in seven distinct fruit samples of Annona muricata ranged from 14 μmol to 226 μmol of AAGs per 100 g fresh pulp (i.e. 0.14 mmol to 1.3 mmol of AAGs per fruit)., Conclusion: A simple, accurate and specific method for quantification of AAGs content was developed and validated for routine application to fruit pulp crude extracts. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Published
2017
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18. The fruit of Annona squamosa L. as a source of environmental neurotoxins: From quantification of squamocin to annotation of Annonaceous acetogenins by LC-MS/MS analysis.

Author

Bonneau N, Baloul L, Bajin Ba Ndob I, Sénéjoux F, and Champy P

Subjects
Asia, Caribbean Region, Chromatography, High Pressure Liquid, Tandem Mass Spectrometry, Acetogenins analysis, Annona chemistry, Fruit chemistry, Furans analysis, Lactones analysis, Neurotoxins analysis
Abstract

Annonaceous acetogenins (AAGs) are neurotoxins possibly responsible for atypical Parkinsonism/dementia clusters, via the consumption of edible Annonaceae fruits. Their presence was investigated in fruit pulps of Annona squamosa from different locations. Qualitative analysis of other AAGs was performed. We here report the identification of squamocin in batches from Asia, the Caribbean Basin and the Indian Ocean. This molecule was quantified by HPLC-UV, evidencing a content of 13.5-36.4mg/fruit. HPLC-ESI-Q-TOF allowed the detection of 25 different raw formulas matching with AAGs. LC-MS/MS methodological development was performed using 4 representative standards. The main AAGs could be annotated, including bullatacin (rolliniastatin-2) and annonacin. This study evidences a remarkable homogeneity for the main AAGs within the species, and discrepancies for minor compounds. These findings indicate that A. squamosa should be considered a risk factor for neurodegenerative disorders., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Published
2017
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19. Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1.

Author

Pautus S, Alami M, Adam F, Bernadat G, Lawrence DA, De Carvalho A, Ferry G, Rupin A, Hamze A, Champy P, Bonneau N, Gloanec P, Peglion JL, Brion JD, Bianchini EP, and Borgel D

Subjects
4-Butyrolactone administration & dosage, 4-Butyrolactone chemistry, 4-Butyrolactone pharmacology, Animals, Binding Sites, Down-Regulation, Drug Evaluation, Preclinical, Fibrinolytic Agents chemistry, Fibrinolytic Agents pharmacology, Humans, Indoleacetic Acids administration & dosage, Indoleacetic Acids pharmacology, Mice, Models, Animal, Models, Molecular, Molecular Docking Simulation, Plasminogen Activator Inhibitor 1 chemistry, Plasminogen Activator Inhibitor 1 genetics, Protein Structure, Secondary, Thrombelastography, 4-Butyrolactone analogs & derivatives, Fibrinolytic Agents administration & dosage, Plasminogen Activator Inhibitor 1 metabolism
Abstract

Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of the tissue type and urokinase type plasminogen activators. High levels of PAI-1 are correlated with an increased risk of thrombotic events and several other pathologies. Despite several compounds with in vitro activity being developed, none of them are currently in clinical use. In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group. Annonacinone was identified in a chromogenic screening assay and was more potent than tiplaxtinin. Annonacinone showed high potency ex vivo on thromboelastography and was able to potentiate the thrombolytic effect of tPA in vivo in a murine model. SDS-PAGE showed that annonacinone inhibited formation of PAI-1/tPA complex via enhancement of the substrate pathway. Mutagenesis and molecular dynamics allowed us to identify annonacinone binding site close to helix D and E and β-sheets 2A.

Published
2016
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20. Chronic consumption of Annona muricata juice triggers and aggravates cerebral tau phosphorylation in wild-type and MAPT transgenic mice.

Author

Rottscholl R, Haegele M, Jainsch B, Xu H, Respondek G, Höllerhage M, Rösler TW, Bony E, Le Ven J, Guérineau V, Schmitz-Afonso I, Champy P, Oertel WH, Yamada ES, and Höglinger GU

Subjects
Animals, Brain drug effects, Cell Line, Humans, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation drug effects, Phosphorylation physiology, Plant Extracts adverse effects, Random Allocation, tau Proteins genetics, Annona adverse effects, Brain metabolism, Fruit and Vegetable Juices adverse effects, Plant Extracts administration & dosage, tau Proteins biosynthesis
Abstract

In the pathogenesis of tauopathies, genetic and environmental factors have been identified. While familial clustering led to the identification of mutations in MAPT encoding the microtubule-associated protein tau, the high incidence of a sporadic tauopathy endemic in Guadeloupe was linked to the plant-derived mitochondrial complex I inhibitor annonacin. The interaction of both factors was studied in the present work in a realistic paradigm over a period of 12 months. Mice over-expressing either human wild-type tau or R406W mutant tau as well as non-transgenic mice received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. HPLC-MS analysis of this juice identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline). After 12 month of juice consumption, several brain regions showed an increased number of neurons with phosphorylated tau in the somatodendritic compartment of R406W mice and, to a much lesser extent, of non-transgenic mice and mice over-expressing human wild-type tau. Moreover, juice drinking was associated with a reduction in synaptophysin immunoreactivity, as well as an increase in 3-nitrotyrosine (3NT) reactivity in all three genotypes. The increase in 3NT suggests that Annona muricata juice promotes the generation of reactive nitrogen species. This study provides first experimental evidence that long-lasting oral ingestion of a widely consumed environmental factor can induce somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild-type tau, and can accelerate tau pathology in R406W-MAPT transgenic mice., (© 2016 International Society for Neurochemistry.)

Published
2016
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21. Antiplasmodial activity of selected medicinal plants used to treat malaria in Ghana.

Author

Komlaga G, Cojean S, Dickson RA, Beniddir MA, Suyyagh-Albouz S, Mensah ML, Agyare C, Champy P, and Loiseau PM

Subjects
Cell Line, Chloroquine pharmacology, Ghana, Humans, Malaria, Falciparum drug therapy, Medicine, Traditional, Plant Leaves chemistry, Plant Roots chemistry, Plasmodium falciparum drug effects, Plasmodium falciparum physiology, Antimalarials pharmacology, Malaria, Falciparum parasitology, Phyllanthus chemistry, Plant Extracts pharmacology, Plants, Medicinal chemistry
Abstract

The use of medicinal plants for the treatment of diseases including malaria is commonplace in Ghanaian traditional medicine, though the therapeutic claims for most plants remain unvalidated. Antiplasmodial activity of the aqueous extracts and successively obtained petroleum ether, ethyl acetate and methanol fractions of the whole Phyllanthus fraternus plant, the leaves of Tectona grandis, Terminalia ivorensis and Bambusa vulgaris, and roots of Senna siamea were studied against Plasmodium falciparum chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains. The aqueous extracts were assessed against human umbilical vein endothelial cells (HUVECs) for cytotoxicity, and the organic solvent fractions against human O(+) erythrocytes for haemolytic effect. Both extracts and fractions demonstrated antiplasmodial activity to varied extents. The aqueous extract of T. ivorensis was the most active (3D7, IC50 0.64 ± 0.14; and W2, IC50 10.52 ± 3.55 μg/mL), and together with P. fraternus displayed cytotoxicity (CC50 6.25 ± 0.40 and 31.11 ± 3.31 μg/mL, respectively). The aqueous extracts were generally selective for 3D7 strain of P. falciparum (selectivity indexes (SIs) ≥3.48) but only that of S. siamea was selective for the W2 strain (SI > 2.1). The organic solvent fractions also displayed antiplasmodial activity with the methanol fractions of P. fraternus and T. grandis, and the fractions of B. vulgaris showing activity with IC50 below 1 μg/mL against P. falciparum 3D7 strain; some fractions showed haemolytic effect but with low to high selectivity indexes (SI ≥ 4). The results while justifying the traditional use of the plant materials in the treatment of malaria, however, suggest their cautious use.

Published
2016
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22. Quantification of the environmental neurotoxin annonacin in Rat brain by UPLC-MS/MS.

Author

Bonneau N, Schmitz-Afonso I, Brunelle A, Touboul D, and Champy P

Subjects
Administration, Oral, Animals, Biotransformation, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Electron Transport Complex I antagonists & inhibitors, Electron Transport Complex I metabolism, Environmental Pollutants administration & dosage, Environmental Pollutants analysis, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors analysis, Enzyme Inhibitors toxicity, Furans administration & dosage, Furans analysis, Injections, Intravenous, Lactones administration & dosage, Lactones analysis, Male, Neurons chemistry, Rats, Wistar, Spectrometry, Mass, Electrospray Ionization, Tandem Mass Spectrometry, Tissue Distribution, Toxicokinetics, Toxins, Biological administration & dosage, Toxins, Biological analysis, Brain metabolism, Environmental Pollutants toxicity, Furans toxicity, Lactones toxicity, Neurons metabolism, Toxins, Biological toxicity
Abstract

The Annonaceous acetogenin annonacin is an environmental neurotoxin identified in the pulp of several fruits of the Annonaceae family, whose consumption was linked to the occurrence of sporadic atypical Parkinsonism with dementia. A method for its quantification in Rat brain homogenates by UPLC-MS/MS in selected reaction monitoring (SRM) mode was developed and validated. This method was applied to the quantitation of annonacin in Rat brain after intravenous (0.5 mg/kg) and oral (10 mg/kg, 100 mg/kg) administration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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23. Validation data for the quantification of the Annonaceous acetogenin annonacin in Rat brain by UPLC-MS/MS.

Author

Bonneau N, Schmitz-Afonso I, Brunelle A, Touboul D, and Champy P

Abstract

Annonaceous acetogenins (AAGs) are environmental neurotoxins from the fruit pulp of several Annonaceae species, whose consumption was linked to the occurrence of sporadic atypical Parkinsonism with dementia. The quantification of the prototypical AAG annonacin in Rat brain homogenates was performed by UPLC-MS/MS in selected reaction monitoring (SRM) mode, using a triple quadrupole mass analyzer. A natural analog of annonacin was used as an internal standard. Analyzed data set of the analytical validation of this method is presented, including stability of the samples, extraction recovery and matrix effect, supporting the results described in the article "Quantification of the environmental neurotoxin annonacin in Rat brain by UPLC-MS/MS" N. Bonneau, I. Schmitz-Afonso, D. Touboul, A. Brunelle, P. Champy (2016) [1].

Published
2016
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24. Development of a SPE/HPLC/DAD method for the determination of antileishmanial 2-substituted quinolines and metabolites in rat plasma.

Author

Desrivot J, Moussa F, Champy P, Fournet A, Figadère B, and Herrenknecht C

Subjects
Animals, Antiprotozoal Agents pharmacology, Male, Protein Binding, Quinolines pharmacology, Rats, Rats, Wistar, Ultrafiltration, Antiprotozoal Agents blood, Chromatography, High Pressure Liquid methods, Leishmania drug effects, Quinolines blood, Spectrophotometry, Ultraviolet methods
Abstract

A SPE/HPLC/DAD method was developed for the in vivo monitoring of three new antileishmanial 2-substituted quinolines under study in our laboratory for the development of an oral treatment. Three phase I metabolites were included in this work for the optimization of the method. Trifunctional tC(18) cartridges (resulting from the reaction of trifunctional silanes with silica surface) were selected among four sorbents tested. Two linear gradients were developed to ensure resolution of metabolites. Recovery of quinolines from rat plasma was comprised between 80.6 and 88.2%. In a drug development perspective, apparent pK(a), lipophilicity and solubility were determined, as well as the extent of plasma protein or albumin binding.

Published
2007
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25. Metabolism of 2-substituted quinolines with antileishmanial activity studied in vitro with liver microsomes, hepatocytes and recombinantly expressed enzymes analyzed by LC/MS.

Author

Desrivot J, Edlund PO, Svensson R, Baranczewski P, Fournet A, Figadère B, and Herrenknecht C

Subjects
Animals, Aryl Hydrocarbon Hydroxylases metabolism, Biotransformation, Cytochrome P-450 CYP1A1 metabolism, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B1 metabolism, Cytochrome P-450 Enzyme System genetics, Drug Stability, Glucuronides metabolism, Glutathione metabolism, Half-Life, Hepatocytes enzymology, Humans, Hydroxylation, In Vitro Techniques, Kinetics, Male, Microsomes, Liver enzymology, Mixed Function Oxygenases metabolism, Molecular Structure, Quinolines chemistry, Quinolines pharmacology, Rats, Rats, Sprague-Dawley, Recombinant Proteins metabolism, Trypanocidal Agents chemistry, Trypanocidal Agents pharmacology, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System metabolism, Hepatocytes metabolism, Leishmania drug effects, Mass Spectrometry, Microsomes, Liver metabolism, Quinolines metabolism, Trypanocidal Agents metabolism
Abstract

Liver microsome and hepatocyte-mediated biotransformation of three oral antileishmanial 2-substituted quinolines were investigated. One quinoline contains an n-propyl group (1) and the other a propenyl chain functionalized at the gamma position either by a nitrile (2) or an alcohol (3). The different isoforms of rat cytochrome P450 responsible for biotransformation of 1 were also investigated. Compounds 2 and 3 mainly reacted with glutathione, preventing further metabolism. Compound 3 however, the reaction being reversible, could be released from glutathione and take alternative reaction pathways. Microsomal incubations of 1 mainly led to hydroxylation of the side chain, involving many cytochromes, predominantly CYP2B1, CYP2A6 and CYP1A1 (at more than 80%). In contrary, minor metabolites hydroxylated on the quinoline ring involved a few cytochromes. The hydroxylated products of 1 were conjugated with glucuronic acid in rat hepatocyte incubations.

Published
2007
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26. Heterocyclic analogues of squamocin as inhibitors of mitochondrial complex I. On the role of the terminal lactone of annonaceous acetogenins.

Author

Duval RA, Lewin G, Peris E, Chahboune N, Garofano A, Dröse S, Cortes D, Brandt U, and Hocquemiller R

Subjects
Acetogenins, Annona enzymology, Electron Transport Complex I metabolism, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Esters chemistry, Fatty Alcohols chemistry, Fatty Alcohols pharmacology, Furans chemistry, Lactones chemistry, Lactones pharmacology, Mitochondria, Heart drug effects, Mitochondria, Heart metabolism, NADH, NADPH Oxidoreductases antagonists & inhibitors, NADH, NADPH Oxidoreductases metabolism, Oxidation-Reduction, Ruthenium chemistry, Seeds metabolism, Substrate Specificity, Annona metabolism, Electron Transport Complex I antagonists & inhibitors, Fatty Alcohols metabolism, Furans pharmacology, Lactones metabolism
Abstract

Heterocyclic analogues of squamocin have been semisynthesized by condensation reactions between squamocin-derived alpha-keto esters and heterodinucleophiles. The strong complex I inhibitory potency of squamocin-benzimidazole, a hybrid derivative, illustrates for the first time the functional analogy existing between the terminal butenolide of annonaceous acetogenins and heteroaromatic substructures of classic inhibitors of the enzyme. This finding supports the categorization of this atypical group of inhibitors as antagonists of the ubiquinone substrates. In addition, competition experiments of squamocin-benzimidazole versus squamocin and rolliniastatin-2 suggest that the binding of this hybrid inhibitor is responsible for a negative allosteric effect at the level of the first ubiquinone-binding site (A site) of mitochondrial complex I. This result supports the existence of a large cooperatively regulated inhibitor/ubiquinone-binding pocket located within the catalytic core of the enzyme, consisting of the association of the previously defined affinity sites A and B.

Published
2006
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27. Semisynthesis and biological activity of aminoacyl triesters of squamocin, an annonaceous acetogenin.

Author

Duval RA, Duret P, Lewin G, Peris E, and Hocquemiller R

Subjects
Cell Line, Esters, Furans chemistry, Humans, Lactones chemistry, Magnetic Resonance Spectroscopy, Spectrometry, Mass, Electrospray Ionization, Submitochondrial Particles drug effects, Annona chemistry, Furans chemical synthesis, Furans pharmacology, Lactones chemical synthesis, Lactones pharmacology
Abstract

A number of aminoacyl triesters of squamocin 1, a cytotoxic acetogenin isolated from the seeds of Annona reticulata, have been synthesized in two to three steps from protected (l)-aminoacids and squamocin 1 using standard coupling/deprotection procedures. These semisynthetic analogs were tested on submitochondrial particles (SMP) for their complex I inhibitory activities, and against KB 3-1 cells in vitro. All triesters derivatives exhibited a complete extinction of activity at the enzymatic level, correlated to a reduced though modulated cytotoxicity in comparison with squamocin 1. This activity can apparently be considered as a function of the amphipathy of the analogs, the more amphiphilic ones being the more cytotoxic.

Published
2005
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28. Semisynthesis of heterocyclic analogues of squamocin, a cytotoxic annonaceous acetogenin, by an unusual oxidative decarboxylation reaction.

Author

Duval R, Lewin G, and Hocquemiller R

Subjects
Cell Cycle drug effects, Cell Line, Tumor, Decarboxylation, Furans chemistry, Humans, Inhibitory Concentration 50, Lactones chemistry, Molecular Structure, Oxidation-Reduction, Furans chemical synthesis, Furans toxicity, Lactones chemical synthesis, Lactones toxicity
Abstract

In addition to two expected pyrazin derivatives, two imidazole analogues of squamocin 1 have been semisynthetised from squamocin derived alpha-ketoesters/alpha-ketoacid, via an unusual condensation-oxidative decarboxylation reaction with 1,2 diamines in presence of acetic acid and oxygen as the key step. Some of these analogues exhibited potent, although significantly reduced cytotoxicities relatively to squamocin 1. In addition, benzimidazole 8 possessed in comparison with the natural acetogenin some interesting cell cycle effects.

Published
2003
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29. Cytotoxicity of 6,16-disubstituted analogues of (-)-vincadifformine.

Author

Lewin G, Hocquemiller R, Schaeffer C, Lambert PH, Léonce S, and Pierré A

Subjects
Animals, Cross-Linking Reagents, Drug Screening Assays, Antitumor, Leukemia L1210 drug therapy, Magnetic Resonance Spectroscopy, Mice, Oxidation-Reduction, Stereoisomerism, Structure-Activity Relationship, Alkaloids chemical synthesis, Alkaloids pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology
Abstract

Eight analogues of (-)-16-chloro-1-dehydro-6S-bromovincadifformine 1 were synthesized and evaluated for cytotoxicity in L1210 cell culture. None of the new compounds was more active than 1 but the modulation at C6, C16 and on the aromatic ring at C10 informs about structure-activity relationships within this series.

Published
2002
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30. Synthesis of a novel series of cytotoxic bisindole alkaloids.

Author

Raoul M, Schaeffer C, Léonce S, Pierré A, Atassi G, Hocquemiller R, and Lewin G

Subjects
Alkaloids chemistry, Aniline Compounds chemical synthesis, Aniline Compounds toxicity, Animals, Antineoplastic Agents chemical synthesis, Cell Cycle drug effects, Dimerization, Dose-Response Relationship, Drug, Indoles chemistry, Inhibitory Concentration 50, Mice, Molecular Structure, Stereoisomerism, Structure-Activity Relationship, Tumor Cells, Cultured, Alkaloids chemical synthesis, Alkaloids toxicity, Aniline Compounds chemistry, Indoles chemical synthesis, Indoles toxicity
Abstract

Original cytotoxic bisindole alkaloids with a 1,2,3,4-tetrahydroquinoline bridge were synthesized by reductive amination with various anilines. The most cytotoxic compounds display a high and dose-dependent cell cycle effect with accumulation in the G1 phase. Influence of substitution of the starting aniline on the reaction and on cytotoxicity of produced dimers was pointed out.

Published
2001
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31. Antiprotozoal activity of aporphine alkaloids isolated from Unonopsis buchtienii (Annonaceae).

Author

Waechter AI, Cavé A, Hocquemiller R, Bories C, Muñoz V, and Fournet A

Subjects
Alkaloids isolation & purification, Animals, Antiprotozoal Agents isolation & purification, Chlorocebus aethiops, Leishmania donovani drug effects, Leishmania major drug effects, Phytotherapy, Plant Stems chemistry, Sterols isolation & purification, Vero Cells, Alkaloids pharmacology, Antiprotozoal Agents pharmacology, Leishmania drug effects, Plant Extracts pharmacology, Sterols pharmacology, Trypanosoma brucei brucei drug effects
Abstract

On a preliminary screening, substantial leishmanicidal activity was observed for the petroleum ether and alkaloidal extracts of the stem bark of Unonopsis buchtienii, the alkaloids and sterols isolated from these were studied. Of the alkaloids, liriodenine exhibited the highest activity against Leishmania major and L donovani (IC100 = 3.12 micrograms/mL). On the other hand, O-methylmoschatoline and the petroleum ether extract without alkaloids showed an interesting in vitro activity against Trypanosoma brucei with an IC100 of 6.25 micrograms/mL. The highest cytotoxic activities were found with the petroleum ether extracts without alkaloids and with all alkaloids isolated (IC50 < 9 micrograms/mL for Vero cell line).

Published
1999
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32. Acetogenins and other compounds from Rollinia emarginata and their antiprotozoal activities.

Author

Février A, Ferreira ME, Fournet A, Yaluff G, Inchausti A, Rojas de Arias A, Hocquemiller R, and Waechter AI

Subjects
Antiprotozoal Agents chemistry, Antiprotozoal Agents pharmacology, Furans chemistry, Furans pharmacology, Lactones chemistry, Lactones pharmacology, Molecular Structure, Spectrum Analysis, Antiprotozoal Agents isolation & purification, Furans isolation & purification, Lactones isolation & purification, Plants, Medicinal chemistry
Abstract

Bioactivity-directed fractionation of the MeOH extract of the stem barks of Rollinia emarginata resulted in the isolation of six compounds, four acetogenins, rolliniastatin-1, sylvaticin, squamocin, and rollidecin B, one lignan, lirioresinol B, and an oxoaporphine, liriodenin. Their structures were determined by spectroscopic analysis and their in vitro leishmanicidal and trypanocidal properties are reported.

Published
1999
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33. Experimental treatment of cutaneous leishmaniasis with argentilactone isolated from Annona haematantha.

Author

Waechter AI, Ferreira ME, Fournet A, Rojas de Arias A, Nakayama H, Torres S, Hocquemiller R, and Cavé A

Subjects
Animals, Female, French Guiana, Lactones chemistry, Lactones isolation & purification, Leishmaniasis, Cutaneous pathology, Leishmaniasis, Cutaneous physiopathology, Male, Mice, Mice, Inbred BALB C, Trypanocidal Agents chemistry, Trypanocidal Agents isolation & purification, Lactones therapeutic use, Leishmania mexicana isolation & purification, Leishmaniasis, Cutaneous drug therapy, Medicine, African Traditional, Plants, Medicinal, Trypanocidal Agents therapeutic use
Abstract

From the hexanic extract of roots of Annona haematantha an alpha,beta-unsaturated delta-lactone was isolated and identified as argentilactone. This compound exhibited in vitro activity against various strains of Leishmania ssp. at 10 micrograms/ml. BALB/c mice infected with Leishmania amazonensis were treated four weeks after infection with argentilactone by oral or subcutaneous routes for 14 days at 25 mg/kg daily. The reference drug, N-methylglucamine antimonate, was administered by subcutaneous injections at 100 mg/kg for 14 days. In these conditions, argentilactone showed the same efficacy as the reference drug, reducing by 96% the parasite loads in the lesion and by 50% the parasite burden in spleen.

Published
1997
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