Background This thesis investigated the efficacy and safety of Bacopa monnieri in improving memory in healthy Australians over the age of 55-years. A review of the literature showed that memory impairment and dementia are increasingly prevalent in the current demographic climate of an ageing population. As well as the pathological cognitive loss of neurodegenerative disease, many older persons are experiencing memory loss as part of the physiological process of ageing. Bacopa monnieri is a herbal medicine used since antiquity in the traditional Ayurvedic medical system of India for its cognitive enhancing effects. A number of pre-clinical and clinical studies support this traditional usage. Laboratory studies have demonstrated antioxidant and cholinergic actions in the brain as well as improved memory and cognitive performance in animal models. Human trials of Bacopa have also demonstrated improved memory performance. Some of these trials are limited by methodological flaws such as lack of blinding, small sample sizes, or use of outcome measurements which are not well validated. However, a small number of well designed human trials provide evidence for efficacy in cognitive and memory performance improvement. The current study was employed to extend on previous findings by assessing the efficacy and safety of Bacopa in the aged population specifically, as it is in this population that memory impairment becomes apparent. Aims 1. To assess the efficacy of Bacopa monnieri in improving memory in healthy Australians over the age of 55-years. 2. To assess whether the use of Bacopa is associated with side-effects Design A 12-week, randomised, double-blind, placebo-controlled, parallel group clinical trial. Participants Participants were self selected from the general population. They were aged 55-years or over at the commencement of the trial. Participants were without dementia, depression or other serious health conditions and did not use psychotropic medications. Intervention Participants were randomised to one of two treatment conditions, either a tableted extract of Bacopa monnieri called Bacomind™ (300mg/day, standardised to contain at least 40% bacosides), or an identical placebo. Participants attended three clinical evaluations: the first an initial screening session, the second a baseline evaluation of neuropsychological function and subjective memory performance at the commencement of the trial and the third, an end-of-trial outcome evaluation at 12-weeks, during which neuropsychological function and subjective memory performance were again assessed along with side-effects and study compliance. Primary Outcome Measures Rey Auditory Verbal Learning Test (AVLT), Rey-Osterrieth Complex Figure Test (CFT), Memory Complaint Questionnaire (MAC-Q), and Trail Making Test (TMT) Results From 136 people who elected to participate, 103 people met study entry criteria and 98 of these commenced the trial. Of these, 81 participants completed the trial and provided evaluable data for the end point analysis. Bacopa monnieri versus placebo significantly improved verbal learning as well as delayed recall as measured by the AVLT (p<.05). Though improvements were noted in the CFT, MAC-Q and TMT, there were no significant differences between placebo and active groups found for these tests. The Bacopa group reported a higher incidence of gastro-intestinal (GIT) side-effects than the placebo group, these predominantly being increased stool frequency, abdominal cramps and nausea. No other significant adverse effects were found. Conclusions A clinical trial was carried out to assess the effects of 12-weeks administration of Bacopa monnieri (300mg/day) on memory performance in people over the age of 55-years. Primary outcome measures were well validated neuropsychological tests that objectively measured verbal and visual memory and a memory complaint questionnaire that measured subjective memory complaints. The results demonstrated that Bacopa significantly improved memory acquisition and retention in older Australians. This concurs with findings from previous human and animal studies, as well as supports traditional Ayurvedic claims and uses. The beneficial effects on memory observed may be due to previously demonstrated antioxidant and cholinergic effects of the herb on the central nervous system. The use of Bacopa was associated with GIT side-effects, particularly increased bowel movements, nausea and abdominal cramping, findings infrequently reported previously. Possible explanations for these side-effects include GIT irritation by the saponin constituents of the herb, or cholinergic stimulation of autonomic and motor responses in the GIT, or a combination of both of these factors. The side-effects observed in the current study provide supportive evidence that Bacopa may increase cholinergic activity in humans. A worthwhile future extension of the current study would be to assess whether the finding of Bacopa’s efficacy for improving memory performance is replicable in populations with either mild cognitive impairment or early dementia.

Background This thesis investigated the efficacy and safety of Bacopa monnieri in improving memory in healthy Australians over the age of 55-years. A review of the literature showed that memory impairment and dementia are increasingly prevalent in the current demographic climate of an ageing population. As well as the pathological cognitive loss of neurodegenerative disease, many older persons are experiencing memory loss as part of the physiological process of ageing. Bacopa monnieri is a herbal medicine used since antiquity in the traditional Ayurvedic medical system of India for its cognitive enhancing effects. A number of pre-clinical and clinical studies support this traditional usage. Laboratory studies have demonstrated antioxidant and cholinergic actions in the brain as well as improved memory and cognitive performance in animal models. Human trials of Bacopa have also demonstrated improved memory performance. Some of these trials are limited by methodological flaws such as lack of blinding, small sample sizes, or use of outcome measurements which are not well validated. However, a small number of well designed human trials provide evidence for efficacy in cognitive and memory performance improvement. The current study was employed to extend on previous findings by assessing the efficacy and safety of Bacopa in the aged population specifically, as it is in this population that memory impairment becomes apparent. Aims 1. To assess the efficacy of Bacopa monnieri in improving memory in healthy Australians over the age of 55-years. 2. To assess whether the use of Bacopa is associated with side-effects Design A 12-week, randomised, double-blind, placebo-controlled, parallel group clinical trial. Participants Participants were self selected from the general population. They were aged 55-years or over at the commencement of the trial. Participants were without dementia, depression or other serious health conditions and did not use psychotropic medications. Intervention Participants were randomised to one of two treatment conditions, either a tableted extract of Bacopa monnieri called Bacomind™ (300mg/day, standardised to contain at least 40% bacosides), or an identical placebo. Participants attended three clinical evaluations: the first an initial screening session, the second a baseline evaluation of neuropsychological function and subjective memory performance at the commencement of the trial and the third, an end-of-trial outcome evaluation at 12-weeks, during which neuropsychological function and subjective memory performance were again assessed along with side-effects and study compliance. Primary Outcome Measures Rey Auditory Verbal Learning Test (AVLT), Rey-Osterrieth Complex Figure Test (CFT), Memory Complaint Questionnaire (MAC-Q), and Trail Making Test (TMT) Results From 136 people who elected to participate, 103 people met study entry criteria and 98 of these commenced the trial. Of these, 81 participants completed the trial and provided evaluable data for the end point analysis. Bacopa monnieri versus placebo significantly improved verbal learning as well as delayed recall as measured by the AVLT (p<.05). Though improvements were noted in the CFT, MAC-Q and TMT, there were no significant differences between placebo and active groups found for these tests. The Bacopa group reported a higher incidence of gastro-intestinal (GIT) side-effects than the placebo group, these predominantly being increased stool frequency, abdominal cramps and nausea. No other significant adverse effects were found. Conclusions A clinical trial was carried out to assess the effects of 12-weeks administration of Bacopa monnieri (300mg/day) on memory performance in people over the age of 55-years. Primary outcome measures were well validated neuropsychological tests that objectively measured verbal and visual memory and a memory complaint questionnaire that measured subjective memory complaints. The results demonstrated that Bacopa significantly improved memory acquisition and retention in older Australians. This concurs with findings from previous human and animal studies, as well as supports traditional Ayurvedic claims and uses. The beneficial effects on memory observed may be due to previously demonstrated antioxidant and cholinergic effects of the herb on the central nervous system. The use of Bacopa was associated with GIT side-effects, particularly increased bowel movements, nausea and abdominal cramping, findings infrequently reported previously. Possible explanations for these side-effects include GIT irritation by the saponin constituents of the herb, or cholinergic stimulation of autonomic and motor responses in the GIT, or a combination of both of these factors. The side-effects observed in the current study provide supportive evidence that Bacopa may increase cholinergic activity in humans. A worthwhile future extension of the current study would be to assess whether the finding of Bacopa’s efficacy for improving memory performance is replicable in populations with either mild cognitive impairment or early dementia.

Natural products as sources of novel therapeutic agents experienced a steady increase from around the turn of the twentieth century until it peaked in the 1970s and 1980s. However since this time pharmaceutical research in natural products has experienced a decline. Despite this trend the natural products industry now seems to be experiencing a revival of sorts. This thesis represents a continuation of the work on the isolation and structure elucidation of potential drug leads from terrestrial fungal sources that the natural products group at the University of Canterbury is engaged in. The known compound, pseurotin A (2.7) and two novel diastereomers, pseurotin A2 (2.8) and pseurotin A3 (2.9) were isolated from the extract of a Penicillium sp. of fungus collected from the foreshore of a beach in Vancouver, Canada. The absolute stereochemistry of pseurotin A2 and proposed absolute stereochemistry for A3 were elucidated using a combination of X-ray crystallography (A2 only), circular dichrosim, oxidative cleavage reactions, and J2-resoved 2D NMR experiments. The extract of an as yet unidentified endophytic fungus has yielded eight novel compounds related to the spirobisnaphthalene class of compounds. These eight compounds fall into to distinct groupings. The spiro-mamakones, distinguished by a structurally unprecedented oxygenated spiro-nonene skeleton, comprise five compounds, spiro-mamakones A-E (3.11, 3.15-3.18). In addition to these naturally occurring compounds, the semi-synthetic compounds, 4-oxo-spiro-mamakone A (3.12) and O-acetyl-spiro-mamakone A (3.21), were also synthesised. spiro-Mamakone A was found to be racemic, while X-ray crystallography and optical rotation revealed spiro-mamakone C (3.15) to be present as an enantiomeric mixture (4S*, 5S*, 9R*). Unfortunately the enantiomeric excess was unable to be elucidated. NOE experiments revealed spiro-mamakone B (3.16) to have the relative stereochemistry 4S*, 5S*, 9S*. The relative stereochemistry of spiro-mamakones D (3.17) (4S*, 5S*, 8S*, 9S*) and E (3.18) (4S*, 5S*, 8S*, 9R*) was proposed from comparison of coupling constant calculations from energy-minimised models with those of the experimentally determined values. The second group, comprising three novel compounds named the mamakunoic acids, mamakunoic acid A-C (3.8, 3.7, 3.10), are characterised by their acid substituted dihydro benzofuran system. The low yield obtained of these compounds, unfortunately prevented their stereochemical elucidation. In addition to structure elucidation, biosynthetic studies on spiro-mamakone A and mamakunoic acid B were also carried out. Analysis of the NMR spectra derived from spiro-mamakone A, labelled with isotopic acetate, revealed a situation complicated by the presence of isotopomers and racemisation, resulting in NMR spectra that were somewhat anomalous in appearance. These irregularities however, were resolved leading to the proposal that spiro-mamakone A was derived from a dihydroxynaphthalene (DHN) intermediate, which proceeds through to spiro-mamakone via an epoxide intermediate. Despite problems with purity and low yields of isotopically labelled mamakunoic acid B, it was proposed that like spiro-mamakone A, it proceeded via a DHN intermediate. The extract derived from a Malaysian Scleroderma sp. was found to contain a new dichlorinated pulvinic acid derivative, methyl-3',5'-dichloro-4,4'-di-O-methylatromentate (4.14), the structure of which was confirmed by X-ray crystallography. In addition three previously reported compounds, 4,4'-dimethoxyvulpinic acid (4.11), methyl-3'-chloro-4,4'-di-O-methylatromentate (4.12) and methyl-4,4'-dimethoxyvulpinate (4.13), were also isolated. The extract of another, as yet unidentified endophytic fungus was found to contain the new acetogenin, 1,5-dihydroxy-6-(2-hydroxyethyl)-3-methoxyacetophenone (5.7), differing from the known compound, 2,4-dihydroxy-6-(2-hydroxyethyl)-3-methoxyacetophenone (5.8) only by virtue of the substitution pattern. The structure of 5.7 was confirmed by X-ray crystallography. The implementation of efficient dereplication procedures is paramount for those working in the field of natural products. The recent advances that have been made in the dereplication process in the natural products group at the University of Canterbury are given using examples from this research and where necessary from other group members.

Thesis (Ph.D.)--Flinders University, Dept. of Chemistry. / Typescript bound. Includes bibliographical references: (p. 360-369) Also available online.

Mémoire (M.Ress.Renouv.) -- Université du Québec à Chicoutimi, 1992. / Document électronique également accessible en format PDF. CaQCU

In this study we evaluated the antinociceptive and anti-inflammatory activities of the stem bark of the species Aspidosperma tomentosum in models of pain and inflammation induced in mice. A A. tomentosum belongs to the family Apocynaceae that has been extensively studied and characterized chemically by the frequent occurrence of alkaloids, some of therapeutic importance, such as vinblastine and vincristine. This species is known as pau-pereiro do campo and was collected in the Brazilian cerrado, in the city of Planaltina the state of Goiás, in May 2004. We assessed the antinociceptive and anti-inflammatory activity of crude ethanol extract obtained by extraction with 20 L of 90% ethanol, fractions obtained by chromatography adapted, according to a solvent gradient of increasing polarity, and the flavonoid isorhamnetin, obtained in the filtration of crude ethanolic extract of stem bark of A. tomentosum. We conducted the following tests: test of writhing induced by acetic acid, hot plate, formalin, ear edema induced by capsaicin, peritonitis induced by thioglycollate 3%. Was also evaluated motility and / or depression of the central nervous system by the test of catalepsy. For statistical analysis we used ANOVA followed by Dunnet test, the tutorial Prisma ®. Values were considered significant when * p <0.05, ** p <0.01 and *** p <0.001. The results were expressed as mean ± standard error of the mean. In the abdominal writhing test induced by acetic acid, ethanol extract and fractions showed higher inhibition between 50.8% to 59.7%, compared with dipyrone. In the hot plate test, the fractions Hex: CHCl3 50%, 100% CHCl3 and CHCl3: MeOH 5% showed an increase in latency of the animal on the hot plate, and this result was reversed in the presence of naloxone. In the test of nociception induced by formalin, the crude ethanol extract and its fractions presented significant results in both phases of testing, when compared to control, and the CHCl3 100% fraction presented better performance in both phases (average latency time of 61s and 75s the first and second phases, respectively). In the test of ear edema induced by capsaicin only the soluble fraction of crude ethanol extract, the fraction of CHCl3: MeOH 10% and isorhamnetin showed no inhibition of edema, where the CHCl3: AcOEt 50% was the most active (64.2% of inhibition of edema). In the trial of peritonitis the crude ethanol extract, the isorhamnetin and the fractions used inhibited cell migration, except the fraction AcOEt 100%. The test result of catalepsy suggests that treatment with the fractions Hex: CHCl3 50%, 100% CHCl3 and CHCl3: MeOH 5% of the isolated species A. tomentosum not alter the motor skills of the animal. The results observed in this study indicate that the species A. tomentosum is able to modulate the antinociceptive and antiinflammatory response. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / No presente trabalho foram avaliadas as atividades antinociceptiva e antiinflamatória da casca do caule da espécie Aspidosperma tomentosum, em modelos de dor e inflamação induzidas em camundongos. A A. tomentosum pertence à família Apocynaceae que vem sendo extensivamente estudada e caracteriza-se quimicamente pela ocorrência frequente de alcaloides, alguns de importância terapêutica, como vimblastina e vincristina. A espécie é conhecida como pau-pereiro do campo e foi coletada no cerrado brasileiro, na cidade de Planaltina no estado de Goiás, em maio de 2004. Foram avaliados as atividades antinociceptiva e antiinflamatória do extrato etanólico bruto, obtido por extração com 20 L de etanol 90%, das frações, obtidas por cromatografia rápida em funil de separação adaptado, com solventes segundo um gradiente crescente de polaridade, e do flavonoide isorramnetina, obtido na filtração do extrato etanólico bruto de casca do caule da espécie A. tomentosum. Foram realizados os seguintes testes: teste das contorções abdominais induzidas por ácido acético, placa quente, formalina, edema de orelha induzido por capsaicina, peritonite induzida por tioglicolato a 3%. Foi também avaliada alteração motora e/ou depressão do sistema nervoso central pelo ensaio de catalepsia. Para a análise estatística utilizou-se ANOVA seguida do teste Dunnet, no tutorial Prisma®. Os valores foram considerados significativos quando *p < 0,05, **p < 0,01 e ***p < 0,001. Os resultados foram expressos como média ± erro padrão da média. No ensaio de contorção abdominal induzida por ácido acético, o extrato etanólico e frações apresentaram uma taxa de inibição entre 50,8% a 59,7%, comparados com a dipirona. No ensaio de placa quente, as frações Hex:CHCl3 50%, CHCl3 100% e CHCl3:MeOH 5% apresentaram aumento no tempo de latência do animal na placa quente, sendo esse resultado revertido na presença da naloxona. No ensaio de nocicepção induzida por formalina, o extrato etanólico bruto e suas frações apresentaram resultados significativos nas duas fases do ensaio, quando comparados ao controle, sendo a fração CHCl3 100% com melhor desempenho nas duas fases (tempo de latência médio de 61s e 75s na primeira e segunda fase, respectivamente). No teste de edema de orelha induzida por capsaicina apenas a fração solúvel do extrato etanólico bruto, a fração CHCl3:MeOH 10% e a isorramnetina não apresentaram inibição do edema, onde o CHCl3:AcOEt 50% foi o mais ativo (64,2% de inibição do edema). No ensaio de peritonite o extrato etanólico bruto, a isorramnetina e as frações utilizadas inibiram a migração celular, exceto a fração AcOEt 100%. O resultado do ensaio de catalepsia sugere que o tratamento com as frações Hex:CHCl3 50%, CHCl3 100% e CHCl3:MeOH 5% obtidas da espécie A. tomentosum não alteram a capacidade motora do animal. Os resultados observados neste estudo indicam que espécie A. tomentosum é capaz de modular a resposta antinociceptiva e antiinflamatória aguda.

Bowdichia virgilioides Kunth, popularly known as "sucupira preta", is used in folk regional medicine to combat inflammation, autoimmune diseases and healing. There are only few scientific studies dealing with its biological activity, especially in regards to the immune system, making it a potential target of scientific research. The aim of this study was to evaluate in vivo the action of the aqueous extract of Bowdichia virgilioides-derived stem bark (EaBv) in cellular and humoral responses. Swiss male mices were used (4-6 weeks), which were administered EaBv orally for 7 consecutive days. Initially using the template of zymosan A showed that treatment with EaBv increased phagocytic capacity of resident peritoneal macrophages. On the peripheral blood leukocytes count, it was observed a decrease in the number of total leukocytes in animals treated with EaBv and this reduction was observed when the differential number of neutrophils counts was performed. However, the increased number of lymphocytes in peripheral blood of animals after treatment. It has been found by the hemagglutination assay EaBv was able to decrease the production of antibodies. The extract stimulated proliferation of lymphocytes which have been obtained from lymph nodes after 7 days of treatment. Also, interfered with the effect of ConA on T lymphocyte proliferation and acted negatively on the action of LPS on the proliferation of B lymphocytes. Furthermore, flow cytometric, it was observed that the EaBv increased expression of TNF-&#945; by T lymphocytes and IL-10 by B lymphocytes. However, expression of TNF-&#945; by B lymphocytes has been modulated negatively by the extract. Together, these results suggest that aqueous extract of Bowdichia virgilioides-derived stem bark possesses a complexe immune activity, acting on the cellular and humoral immune responses. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Bowdichia virgilioides Kunth, popularmente conhecida como sucupira-preta , é espécie utilizada na medicina popular regional no combate a inflamação, doenças auto-imunes e cicatrizante. Ainda são escassos os estudos que tratam da sua atividade biológica, principalmente em relação ao sistema imunológico, o que a torna um alvo em potencial de investigações científicas. O objetivo desse trabalho foi avaliar in vivo a ação do extrato aquoso da casca do caule da Bowdichia virgilioides (EaBv) na resposta imunológica celular e humoral. Foram utilizados camundongos Swiss (4-6 semanas) machos, aos quais foi administrado por via oral o EaBv durante 7 dias consecutivos. Inicialmente, utilizando o modelo de zimosan A demonstrou-se que o tratamento com EaBv aumentou a capacidade fagocítica de macrófagos peritoneais residentes. Na contagem de leucócitos do sangue periférico, observou-se uma diminuição no número de leucócitos totais nos animais tratados com EaBv e esta diminuição foi evidenciada no número de neutrófilos quando realizada a contagem diferencial. No entanto, o número de linfócitos aumentou no sangue periférico dos animais após o tratamento. Verificou-se pelo ensaio de hemaglutinação que o EaBv foi capaz de diminuir a produção de anticorpos. O extrato estimulou a proliferação dos linfócitos totais que foram obtidos dos linfonodos mesentéricos após os 7 dias de tratamento. Além disso, interferiu na ação da concanavalina A sobre a proliferação de linfócitos T, e agiu negativamente na ação do lipopolissacarídeo sobre a proliferação de linfócitos B. Ainda, por citometria de fluxo, observou-se que o EaBv aumentou a expressão das citocinas TNF-&#945; nos linfócitos T e IL-10 nos linfócitos B. Entretanto, a expressão de TNF-&#945; pelos linfócitos B foi modulado negativamente pelo extrato. Em conjunto, os resultados sugerem que o extrato aquoso da casca do caule Bowdichia virgilioides possui uma atividade imunológica complexa, agindo sobre as respostas imunes celular e humoral.

Este trabalho descreve o estudo do metabolismo secundário em folhas diferenciadas e em suspensões celulares de Piper crassinervium (Piperaceae). Este estudo foi monitorado pela análise do extrato de folhas por CLAE, assim como pela comparação entre os diferentes tecidos desta espécie (folhas, caule e raízes). Do extrato das folhas foram isoladas duas flavanonas, duas hidroquinonas preniladas e uma hidroquinona com um endoperóxido na cadeia lateral. A análise do óleo volátil das folhas através de CG e CG-EM, revelou a presença de trinta e seis componentes, sendo majoritários o germacreno-D (10,05%) seguido por &#946;-cariofileno (9,91 %) e 6-metil-5-hepten-2-ona (7,47%). Todas as substâncias isoladas foram submetidas ao ensaio antifúngico bioautográfico contra Cladosporium sphaerospermun, sendo que as flavanonas, as duas hidroquinonas e o óleo volátil mostraram-se ativos. As suspensões celulares foram desenvolvidas a partir de calos, iniciados a partir de ápices, em meio B5 modificado, contendo ácido naftalenoacético (ANA) e 6-benzilamino purina (BAP) como reguladores de crescimento. As células não produziram flavonóides, mas alcalóides do tipo aristolactamas, que são parcialmente excretados para o meio de cultura. A curva de crescimento estabelecida para as células foi analisada quanto à atividade específica da fenilalanina amônia-liase (PAL), à variação do pH e o acúmulo dos alcalóides. Alguns experimentos de eliciação demonstraram respostas positivas face ao uso de luz UV, adição de L-fenilalanina e uso de extratos de levedura. / The present work studies the secondary metabolism in leaves of Piper crassinervium (Piperaceae) and in its cell suspension culture as well. The profile of secondary compounds in differenciatted and undifferenciated tissues were evaluated by HPLC. The aerial parts of Piper crassinervium yielded two flavanones and three prenylated hydroquinones, one having an endoperoxide group in the side chain. The analysis of the volatile oil of Piper crassinervium by GC-MS allowed the identification of 36 compounds, germacrene-D (10,05%), &#946;-cariofilene (9,91 %) and 6-methyl-5-heptene-2-one (7,47%) being detected as the major ones. Ali isolated substances were evaluated using a bioautography technique against the fungus Cladosporium sphaerospermun. The isolated flavanones, two hydroquinones and the essential oil were found to be active against the fungus. The cell suspensions had their growth curve established on basis of the dry weight and pH variations. The cells were showed to accumulate several aristolactams alkaloids instead. Determinations of these alkaloids by HLPC indicated that the cells excreted them partially to the culture media. Determinations of specific activity of PAL and concentration of alkaloids during the growth cycle were further performed. Additional experiments revealed that UV light and the addition of either phenylalanine or yeast extract cause elicitation response with increased production of alkaloids.

Les ellagitannins C-arylglucosidiques sont des composés polyphénoliques issus du métabolisme spécialisé de nombreuses plantes, en particulier celles appartenant à la famille des Fagacées comme le chêne et le châtaignier. La vescaline qui appartient à cette famille de composés exhibe d’intéressantes propriétés biologiques, notamment antivirales et antitumorales. Plus précisément elle inhibe la topoisomérase 2α, une enzyme ciblée par les chimiothérapies utilisées contre le cancer, et possède également une activité contre les filaments d’actine du cytosquelette. La structure particulièrement unique de la vescaline comporte un motif NonaHydroxyTriPhénoyle (NHTP) lié par une liaison C-arylglucosidique à un coeur D-glucose en forme ouverte. La synthèse totale de différents membres de cette classe de polyphénols d’origine végétale, dont celle de la vescaline, constituait l’objectif principal de cette thèse. Les voies d’accès à ces cibles exploitent en partie des méthodes développées précédemment lors de la synthèse totale de l’épipunicacortéine A 5-O-dégalloylée et sont complétées par de nouvelles méthodologies de synthèse. Ainsi, la méthode et le rendement de l’étape de C-arylglucosidation ont été améliorés et des conditions efficaces de couplage terarylique intramoléculaire entre un motif HexaHydroxyDiPhénoyle (HHDP) et une unité galloyle ont été élaborées. En adaptant la stratégie mise au point pour la synthèse totale de la vescaline, trois ellagitannins C-arylglucosidiques supplémentaires ont été préparés : la punicacortéine A, l’épipunicacortéine A et la castaline. / C-arylglucosidic ellagitannins are polyphenolic compounds biosynthesized through the secondary metabolism of various plants, in particular from the Fagaceae family such as oak and chestnut. Vescalin, which belongs to this class of plant polyphenols, displays interesting biological activities, with antiviral and antitumoral properties. More specifically, it inhibits topoisomerase 2α, a targeted enzyme in chemotherapy used in cancer treatment, and have also an activity against the cytoskeletal filamentous actin. Unique structure of vescalin displays a NonaHydroxyTriPhenoyl moiety (NHTP) linked to an open chain D-glucose with a C-arylglucosidic bond. The total synthesis of vescalin constitutes the main goal of this doctoral work. Synthetic routes employ in part chemical methods previously used for the total synthesis of 5-O-desgalloylepipunicacortein A in addition to new methodologies. Therefore, the C-arylglucosidation method and chemical yield have been improved and an efficient intramolecular terarylic coupling between a HexaHydroxyDiPhenoyl moiety (HHDP) and a galloyl unit has been developed. Taking advantage of the synthetic strategy elaborated for vescalin total synthesis, three additional C-arylglucosidic ellagitannins were obtained: punicacortein A, epipunicacortein A and castalin.

Made available in DSpace on 2014-06-11T19:35:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-06-18Bitstream added on 2014-06-13T21:07:21Z : No. of bitstreams: 1 amaral_fp_dr_araiq.pdf: 4513783 bytes, checksum: e99f12bcbcd5a5642dd150965f5e0fd8 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / No Brasil, 31 espécies vegetais de Paepalanthus foram registradas no Estado de Minas Gerais, no topo da Serra do Espinhaço, o principal centro de diversidade de Eriocaulaceae do Brasil e mais de 400 espécies de Paepalanthus e estão distribuídas geograficamente do estado do Amazonas a São Paulo. Apesar do grande número de espécies existentes em Eriocaulaceae, a sua peculiar composição química, aliadas às importantes atividades biológicas das substâncias isoladas, existem ainda muitas espécies que não possuem estudos, como no caso de Paepalanthus geniculatus. Portanto, neste trabalho, o extrato metanólico dos capítulos de Paepalanthus geniculatus (Bong.) Kunth foi estudado, utilizando HPLC-ESIMSn. As substâncias foram posteriormente isoladas do extrato metanólico e identificadas por RMN mono e bi-dimensionais. Com estas técnicas analíticas, foi possível identificar a presença de dezenove substâncias fenólicas, destas onze inéditas, sendo quinze flavonóides e quatro naftopiranonas que auxiliará na taxonomia da família. Um flavonol glicosilado ciclodimérico ligado a uma unidade truxilato, também inédito foi isolado e identificado por métodos espectroscópicos e espectrométricos. Alguns flavonóides exibiram forte atividade antioxidante e nenhuma das substâncias apresentou efeito citotóxico significativo em células humanas cancerosas de próstata / In Brazil, 31 plant species of Paepalathus were registered in the State of Minas Gerais, at the top of the Espinhaço, the main center of diversity of Eriocaulaceae in Brazil and over 400 Paepalanthus are distributed geographically from the state of Amazonas to São Paulo. Despite the large number of species existing in Eriocaulaceae, its peculiar chemical composition, which has greatly aided in the taxonomy of the family, combined with the biological activities of isolated substances, there are still many species that have no studies, as in the case of Paepalanthus geniculatus. Therefore, in this work the methanol extract of the capitulae from Paepalanthus geniculatus (Bong.) Kunth were studied. An analytical approach based on HPLC-ESI-MSn was applied to obtain the metabolite profile of this extract and led to the rapid identification of nineteen polyphenolic compounds, eleven unpublished, comprising fifteen flavonoids and four naphthopyranones. The substances were then isolated and identified by NMR mono and bidimensional. A glycosylated cyclodimeric flavonol bonded to a truxilate unit, also unpublished, was isolated and identified by spectroscopic and spectrometric methods. Some flavonoids showed strong antioxidant activity and none of the substances showed significant citotoxic effect in human prostate cancer cells