Isolement et caractérisation des saponosides de plantes de la famille des Alliaceae, Caryophyllaceae et Polygalaceae, et évaluation de leurs activités cytotoxiques sur cellules tumorales

Cette thèse s inscrit dans le cadre de la thématique du laboratoire de Pharmacognosie de l UFR Pharmacie, au sein de l Université de Bourgogne. Elle vise essentiellement la recherche de molécules d origine végétale issue de la biodiversité tropicale dotées d une activité antitumorale, dont principalement les saponines. Ce sont des glycosides triterpéniques ou stéroïdiques connus pour leurs nombreuses propriétés pharmacologiques. L étude de 6 espèces végétales appartenant à 3 familles à savoir Acanthophyllum elatius, A. lilacinum, A. sordidum et Arenaria montana (Caryophyllaceae), Securidaca welwitschii (Polygalaceae) et Allium schoenoprasum (Alliaceae) a conduit à l isolement et à la caractérisation de 24 glycosides naturels. Il s agit de 13 saponines triterpéniques parmi lesquelles 10 sont de structure nouvelle ainsi que 11 saponines stéroïdiques dont 7 nouvelles. Les structures ont été élucidées principalement par l utilisation de la RMN 2D ainsi que la spectrométrie de masse. 10 des 24 molécules isolées ont été testées en vue d évaluer leurs activités cytotoxiques sur deux lignées cellulaires cancéreuses coliques (HT-29 et HCT 116). Nos résultats montrent que 9 d entre elles possèdent une activité cytotoxique significative. Des relations structure/activité ont été ainsi proposées.This thesis was realized in the laboratory of Pharmacognosy, in the Pharmacy section of the Bourgogne University. The main theme of this laboratory is the research of natural saponins from the tropical biodiversity, with antitumoral activities. These molecules are triterpenic or steroidic glycosides, well known for their various pharmacological activities. The study of 6 species belonging to 3 different families : Acanthophyllum elatius, A. lilacinum, A. sordidum and Arenaria montana (Caryophyllaceae), Securidaca welwitschii (Polygalaceae) and Allium schoenoprasum (Alliaceae), led to the isolation and characterization of 24 natural glycosides. Among them, 13 were triterpenic saponins with 10 new structures and 11 were steroidic saponins with 7 new structures. The spectral analysis was achieved using mainly 2D NMR and mass spectrometry. The cytotoxic activities of 10 isolated compounds were evaluated on 2 strains of human colon cancer cells (HT-29 et HCT 116) and 9 were active ones. Structure/activity relationships were also proposed.DIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Etude chimique et biologique de saponines isolées de trois espèces malgaches appartenant aux familles des Caryophyllaceae, Pittosporaceae et Solanaceae

Cette thèse s inscrit dans le cadre de la thématique du Laboratoire de Pharmacognosie de l UFR Pharmacie, au sein de l Université de Bourgogne. Elle vise essentiellement la recherche de molécules d origine végétale principalement des saponines biologiquement actives issues de la biodiversité tropicale. Dans ce contexte l étude de plantes malgaches, Polycarpaea corymbosa Lamk. (CARYOPHYLLACEAE), Pittosporum verticillatum Bojer subsp. verticillatum (PITTOSPORACEAE), Solanum incanum L. et S. heteracanthum Dunal. (SOLANACEAE) a conduit à l isolement de quinze glycosides naturels par les techniques de chromatographie solide-liquide, de chromatographie liquide à moyenne pression, de flash chromatographie, et de chromatographie liquide sous vide. Les structures ont été élucidées principalement par les techniques spectroscopiques de RMN-1D et -2D, et de spectrométrie de masse. Il s agit de neuf saponines triterpéniques de type oléanane, parmi lesquelles sept sont des nouveaux composés naturels, ainsi que cinq saponines stéroïdiques de type spirostane et furostane, dont une nouvelle, et un glycoalcaloïde stéroïdique connu. Treize molécules isolées ont été testées en vue d évaluer leurs activités cytotoxiques sur six lignées cellulaires cancéreuses humaine et animale. Nos résultats montrent que quatre d entre elles possèdent une cytotoxicité significative sur les lignées HT-29, HCT 116, SW480, DU145, EMT6, et H9c2.This thesis was carried out in the Laboratory of Pharmacognosy, in the Pharmacy section of the University of Burgundy. The principal theme of this laboratory is the research of natural compounds from tropical biodiversity, mainly saponins. In this context, the study of Malagasy plants, Polycarpaea corymbosa Lamk. (CARYOPHYLLACEAE), Pittosporum verticillatum Bojer subsp. verticillatum (PITTOSPORACEAE), Solanum incanum L. and S. heteracanthum Dunal. (SOLANACEAE) led to the isolation of fifteen natural glycosides by column chromatography, medium pressure liquid chromatography, flash chromatography, and vacuum liquid chromatography. The structures were elucidated mainly by the use of spectroscopic techniques, NMR-1D and -2D, and mass spectrometry. The compounds were characterized as nine triterpene saponins of the oleanane type, among them seven are new natural compounds, five steroid saponins of the spirostane or furostane type, among them one new, and one known steroid glycoalkaloid. Thirteen of compounds were tested for cytotoxicity against six human and animal cancer cell lines. Our results show that four of them have significant cytotoxicity on cell lines HT-29, HCT 116, SW480, DU145, EMT6, and H9c2.DIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Isolement et caractérisation des saponosides de trois plantes de la famille des araliaceae et dracaenaceae et évaluation de leurs activités cytotoxiques sur cellules tumorales

L intérêt des substances d origine naturelle, potentiellement anti-tumorales nous a amené à nous intéresser aux saponines triterpéniques et stéroïdiques de plantes issues de la biodiversité africaine de la famille des Araliaceae et des Dracaenaceae. En effet, des études antérieures menées sur quelques plantes de ces deux familles ont conduit à l obtention de molécules complexes et originales possédant d excellentes propriétés cytotoxiques, immuno-modulatrices, anti-inflammatoires. Au vu de ces résultats nous avons entrepris des investigations pharmaco-chimiques sur Cussonia arborea (Araliaceae), Dracaena deisteliana et Dracaena arborea (Dracaenaceae), plantes médicinales couramment utilisées en pharmacopée traditionnelle africaine pour traiter différentes maladies. Les travaux menés ont conduit à l isolement de 31 composés purs en utilisant les différentes techniques analytiques du laboratoire notamment les diverses techniques de chromatographie liquide successive à pression atmosphérique, moyenne pression et flash chromatographie sur silice en phase normale et en phase inverse. Les structures ont été déterminées par les méthodes de spectrométrie de masse en source FAB et de spectroscopie de RMN 1D et 2D (COSY, TOCSY, NOESY, HMBC et HSQC). Parmi les 07 composés purs obtenus des écorces de Cussonia arborea, 5 sont des nouvelles saponines triterpéniques dont un dérivé de l acide ursolique, un dérivé de l hédéragénine et trois dérivés de l acide oléanolique, tous disubstitués en position 3 et 28 par des chaînes oligosaccharidiques. 13 composés purs sont obtenus à partir des feuilles de Cussonia arborea, dont 7 nouvelles saponines triterpéniques dérivés de l acide ursolique, de l acide 23-hydroxyursolique, de l hédéragénine et de l acide oléanolique dont 04 d entre elles sont obtenues sous forme de mélanges inséparables d isomères acide oléanolique/acide ursolique et hédéragénine/acide 23-hydroxyursolique. A partir des écorces de Dracaena arborea et des tiges de Dracaena deisteliana, nous avons isolé et caractérisé 10 saponines stéroïdiques dont 4 nouvelles et une sapogénine. Les activités de certains de ces produits purs ont été évaluées sur deux lignées de cellules cancéreuses coliques humaines HCT 116 et HT-29.The interest of the substances from natural origin, potentially antitumor led us to interest in triterpenoid and steroidal saponins of plants from the African biodiversity belonging to the Araliaceae and Dracaenaceae families of plants. Indeed, of the former studies undertaken on some plants of these two families led to obtaining complex and original molecules having excellent cytotoxic, immuno-modulating, anti-inflammatory properties. Within sight of these results we undertook pharmaco-chemical investigations on Cussonia arborea (Araliaceae), Dracaena deisteliana, and Dracaena arborea (Dracaenaceae), medicinal plants usually used in african traditional pharmacopeia to treat various diseases. The work led to the isolation of 31 pure compounds by using the various analytical techniques in particular the various chromatography techniques (CC, MPLC, TLC, flash) on silica gel, normal and reversed phases. The structures were determined by the methods of mass spectrometry (FAB, ESI, IE) and 1D (1H and 13C) and 2D (COSY, TOCSY, NOESY, HMBC and HSQC) NMR spectroscopy. Among the 07 pure compounds obtained of the barks of Cussonia arborea, 5 are new triterpenoid saponins derivatives of ursolic acid, hederagenin and three derived from the acid oleanolic, all disubstituted in position 3 and 28 by oligosaccharidic chains. 13 pure compounds were obtained from leaves of Cussonia arborea, seven of which are new triterpenoid saponins derivatives of oleanolic acid, ursolic acid, hederagenin and 23-hydroxyursolic acid of which four were obtained as mixtures of isomers oleanolic acid/ursolic acid and hederagenin/23-hydroxyursolic acid. From the bark of Dracaena arborea and stem of Dracaena deisteliana, we isolated and characterized ten steroidal saponins including 4 new and sapogenin. The activities of some of these pure products were evaluated on two cancerous lines human colic cells HCT 116 and HT-29.DIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Triterpene saponins from wisteria floribunda "macrobotrys" and "rosea"

Five oleanane-type saponins were isolated from two cultivars of Wisteria floribunda (Willd.) DC. (Fabaceae): From the roots of Wisteria floribunda "macrobotrys", one new oleanane derivative elucidated as 3- O-β-D-xylopyranosyl-(1→2)-β-D-glucuronopyranosyl-22- O-acetyl-3p,22p,24-trihydroxyolean-12-en-30-oic acid, and two known glycosides, and from the roots of Wisteria floribunda "rosea", two known ones. Their structures were elucidated by a detailed 600 MHz NMR analysis including 1D and 2D NMR (1H, 13C, COSY, TOCSY, ROESY, HSQC, HMBC) experiments and mass spectrometry. Chemotaxonomic conclusions were proposed

Two New Retigerane-Type Sesterterpenoids from the Lichen Leprocaulon microscopicum

International audienceTwo new sesterterpenes, 1 and 2, have been isolated from the lichen Leprocaulon microscopicum. In addition to classic chromatographic methods, a liquid-liquid chromatography technique, namely centrifugal partition chromatography (CPC) was applied for the purification of compound 2. The structures were determined by analyses of mass spectrometry and 1D- and 2D-NMR data. The relative configuration of the isolated compounds was assigned on the basis of 2D-NOESY experiments. The two compounds possess a rare pentacyclic carbon skeleton typical for lichen metabolism, and quite unusual in the vegetal kingdom

Triterpenoid saponins from the stem bark of pentaclethra eetveldeana

Two previously undescribed triterpenoid saponins together with 4 known ones were isolated from the stem bark of Pentaclethra eetveldeana De Wild. & Th. Dur. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR experiments in combination with mass spectrometry as 3- O-β- d -glucopyranosyl- (1→2)- [β- d -glucopyranosyl- (1→3)]-β- d -glucopyranosyl- (1→4)- β- d -glucopyranosyl- (1→3)-α- l -rhamnopyranosyl- (1→2)-[β- d-glucopyranosyl- (1→4)]-α- l -arabinopyranosyloleanolic acid and 3- O -β- d -glucopyranosyl- (1→2)-[β- d -glucopyranosyl- (1→3)]-β- d -glucopyranosyl- (1→4)-β- d -glucopyranosyl- (1→3)- α -l -rhamnopyranosyl- (1→2)-[β- d -glucopyranosyl- (1→4)]-α- l -arabinopyranosylhederagenin. © The Author(s) 2019

Triterpenoid saponins from the root bark of haplocoelum congolanum

peer reviewedTwo undescribed triterpenoid saponins together with 5 known ones were isolated from the root bark of Haplocoelum congolanum Hauman. Their structures were elucidated by spectroscopic methods including one-dimensional and two-dimensional nuclear magnetic resonance experiments in combination with mass spectrometry as 3-O-(4-O-[3-hydroxy-3-methylglutaryl])-α-l-arabinopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→4)]-α-l-arabinopyranosyloleanolic acid and 3-O-α-l-arabinofuranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→4)]-α-l-arabinopyranosyloleanolic acid. © The Author(s) 201

Management of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines: Consensus of an expert panel on behalf of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition

More than 360 million persons worldwide (6% of the world population) are chronically infected by the hepatitis B Virus (HBV). Although the incidence of HBV infection has dramatically declined since the implementation of universal immunization programs in several countries and blood-donor screening, a significant number of children are still infected each year, often developing chronic infection and requiring appropriate followup [1]. Despite a rather benign course of chronic hepatitis B (CHB) during childhood and adolescence, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma (HCC), respectively, before adulthood [2,3]. Such a risk for HCC rises to 9-24% when considering the whole lifetime, with an incidence of cirrhosis of 2-3% per year [4,5]. Worldwide universal vaccination remains the goal for eliminating HBV infection and its complications. Treatment of CHB in childhood has been hampered by the chronic delay in licensing new drugs for pediatric use. Safe and effective antiviral therapies are available in adults, but few are labeled for the use in children, and an accurate selection of whom to treat and the identification of the right timing for treatment are needed to optimize response and reduce the risk of antiviral resistance. Although several guidelines on the management of adult patients with CHB have been published by major international societies, the clinical approach to infected children is still evolving, and is mostly based on consensus of expert opinion [6-9]

COVID-19: Is There Evidence for the Use of Herbal Medicines as Adjuvant Symptomatic Therapy?

Background: Current recommendations for the self-management of SARS-Cov-2 disease (COVID-19) include self-isolation, rest, hydration, and the use of NSAID in case of high fever only. It is expected that many patients will add other symptomatic/adjuvant treatments, such as herbal medicines. Aims: To provide a benefits/risks assessment of selected herbal medicines traditionally indicated for “respiratory diseases” within the current frame of the COVID-19 pandemic as an adjuvant treatment. Method: The plant selection was primarily based on species listed by the WHO and EMA, but some other herbal remedies were considered due to their widespread use in respiratory conditions. Preclinical and clinical data on their efficacy and safety were collected from authoritative sources. The target population were adults with early and mild flu symptoms without underlying conditions. These were evaluated according to a modified PrOACT-URL method with paracetamol, ibuprofen, and codeine as reference drugs. The benefits/risks balance of the treatments was classified as positive, promising, negative, and unknown. Results: A total of 39 herbal medicines were identified as very likely to appeal to the COVID-19 patient. According to our method, the benefits/risks assessment of the herbal medicines was found to be positive in 5 cases (Althaea officinalis, Commiphora molmol, Glycyrrhiza glabra, Hedera helix, and Sambucus nigra), promising in 12 cases (Allium sativum, Andrographis paniculata, Echinacea angustifolia, Echinacea purpurea, Eucalyptus globulus essential oil, Justicia pectoralis, Magnolia officinalis, Mikania glomerata, Pelargonium sidoides, Pimpinella anisum, Salix sp, Zingiber officinale), and unknown for the rest. On the same grounds, only ibuprofen resulted promising, but we could not find compelling evidence to endorse the use of paracetamol and/or codeine. Conclusions: Our work suggests that several herbal medicines have safety margins superior to those of reference drugs and enough levels of evidence to start a clinical discussion about their potential use as adjuvants in the treatment of early/mild common flu in otherwise healthy adults within the context of COVID-19. While these herbal medicines will not cure or prevent the flu, they may both improve general patient well-being and offer them an opportunity to personalize the therapeutic approaches