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Lorente, Crivillé Adriana. "Marine Natural Products. Synthesis and structure determination." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/279367.
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Natural products from terrestrial plants and microorganisms have long been a traditional source of drugs. For centuries humans have been looking on their environment for medicines to treat illnesses. But unlike terrestrial sources, marine habitat has not been so extensively studied; this field awaited refinements in technologies to collect the source organisms, and development of more advanced analytic techniques to better understand the more complex isolated compounds. Since 1950s this field has suffered an exponential push; considering that water covers around a 70% of the earth’s surface, and 32 of the 33 animal phyla are represented in aquatic media, marine habitat represents an extensive source of new bioactive molecules.
Synthesis represents a powerful tool to use on our behalf for structure determination and supply of material for clinical tests on the development of new bioactive drugs. This thesis is focused on the synthesis and structure determination of bioactive compounds isolated from marine habitat: barmumycin and phormidolides B-D. Our strategy lied on the identification of the target by comparison of the available data from the natural product with data of our synthetic compounds.
Barmumycin was isolated from an extract of a marine actinomycete and found to be cytotoxic against various human tumor cell lines. Macrolactone 1 was assigned on the basis of 1H and 13C NMR spectroscopy. Compound 1 was synthesized by two different routes. The main goal of both our synthesis is the alkylation of a weak nucleophilic aniline by this two different methods, which are based on a reductive amination and on a nucleophilic substitution.
However, major spectroscopic differences between isolated barmumycin and 1 led to revision of the proposed structure. New structure 2, based on a pyrrolidine with an exocyclic double bond linked to an aromatic ring by an amide bond, was proposed. On the basis of the enantioselective synthesis of this new compound, and subsequent spectroscopic comparison of it to an authentic sample of barmumycin, the structure of the natural compound was indeed confirmed as that of 2.
Polyketide macrolides are a class of secondary metabolites with interesting biological activities and complex structure and stereochemistry. A general overview of THF-containing macrolactones has been compiled, a class of compounds with high potential as drug candidates. Described are isolation, structure determination and the described synthesis up to 2012.
Phormidolides B-D are polyketide macrolides related to oscillariolide and phormidolide A. These compounds were isolated from an active organic extract of a sponge of the Petrosiidae family and presented antitumor activity. The planar structure of Phormidolides B-D was determined on the basis of comparison of the spectra of the natural product with oscillariolide and phormidolide A and with the study of NMR spectra of isolated compounds. The relative stereochemistry of the macrocyclic core was only determined for 4 out of the 6 stereocenters of the macrocycle. The next target of this thesis is the enantioselective synthesis of the macrocyclic core of phormidolides B-D.
The best synthetic pathway to the synthesis of the macrolide core of phormidolides B-D was selected with a not-stereoselective synthetic study. A strategy based on an olefin metathesis was discarded. On the other hand a strategy based on a Julia-Kocienski olefination completed the preparation of the macrocycle as a mixture of diasteromers.
A robust and efficient methodology for the enantioselective synthesis of the macrolide core of phormidolides B-D was developed from the Julia-Kocienski olefination route. The strategy is versatile and can be used for the synthesis of the different diastereomers of the macrocycle making the appropriate changes in the starting materials and chiral inductors. The selective synthesis of the Z-trisubstituted double bond present on the macrocyclic core of phormidolides B-D was the objective of an optimization process that culminated with the use of a 1-(tert-butyl)tetrazolyl sulfone to succesfully afford the formation of the endocyclic alkene with excellent stereoselectivity.
It is a fact that the discovery of New Molecular Entities (NME) requires innovation, new ideas and processes. Scientists have learned over the years how to overcome the problems often associated with marine derived natural products development and this work is one more example of this scenario.Els productes naturals extrets de plantes i organismes terrestres han estat durant molts anys font d’inspiració per a la preparació de fàrmacs. Per contra el medi marí no ha rebut tanta atenció, la química dels productes naturals marins ha hagut d’esperar que les tecnologies es modernitzessin per facilitar la recol•lecció de mostres i la determinació estructural dels productes extrets, que presenten molta més complexitat estructural que els productes d’origen terrestre. En els últims 50 anys, aquest camp ha estat objecte de gran interès ja que representa una font de noves molècules bioactives, amb estructures i mecanismes d’acció diferents dels coneguts. En aquesta tesi s’ha treballat en dos projectes focalitzats en l’estudi de molècules d’origen marí com a fàrmacs, utilitzant la síntesi com a eina en els primers estadis de desenvolupament ja que la quantitat aïllada de les fonts naturals només serveix per fer una primera aproximació a estructura i activitat. La barmumicina és un producte natural amb activitat biològica del que s’ha confirmat l’estructura gràcies a la síntesi. El compost que es va determinar en la primera assignació s’ha obtingut per síntesi i s’ha comparat amb el producte natural duent a la conclusió que l’estructura no era la correcta. La reassignació i síntesi d’una nova molècula proposada ha confirmat la identitat d’aquest producte natural. Les formidolides B-D són productes naturals d’alta complexitat estructural. S’ha desenvolupat la síntesi del fragment macrocíclic de les formidolides B-D, abordant dues aproximacions per a la formació de l’alquè trisubstituit; una basada en una metàtesi d’olefines i l’altra en una olefinació de Julia-Kocienski. La segona ruta s’ha seleccionat com a ruta per adaptar a procediments estereoselectius. Adaptant aquesta estratègia, s’ha desenvolupat una metodologia que permet sintetitzar eficaçment i de forma enantioselectiva el macrocicle de les formidolides B-D; l’estratègia és versàtil, ja que canviant els materials de partida o els auxiliars quirals es pot dirigir la síntesi cap al diastereòmer desitjat. El punt clau de la síntesi ha estat la formació del doble enllaç trisubstituitZ amb bon rendiment i selectivitat, pel qual s’ha dut a terme una optimització del procés. S’han sintetitzat tres estereoisòmers i la comparació dels espectres de RMN del producte natural i els sintètics ha permès establir la configuració relativa dels esterocentres que presenta la macrolactona del producte natural. Els resultats presentats demostren la utilitat de la síntesi en el desenvolupament de productes naturals, ja sigui en la determinació d’estructura, estereoquímica o en la producció en sí.
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Camou-Arriola, Fernando Alberto Josue. "Structure determinations of natural products and related molecules." Diss., The University of Arizona, 1989. http://hdl.handle.net/10150/184773.
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Structures were determined for 48 new natural products and several related compounds by NMR methods. One new natural product and two unnatural product structures were determined by X-ray diffraction. Molecular mechanics calculations on two indoles related to the neurotransmitter serotonin and on some synthetic cyclophanes were used to gain information about their preferred conformations. Considerable time is wasted redetermining the structures of known natural products when they are encountered in new sources. To help alleviate this problem, a database which searches on proton NMR chemical shifts was developed.
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Elsässer, Brigitta. "Investigation on structure-bioactivity relationship and determination of the absolute configuration of natural products." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974404187.
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Dyson, Bryony Sara. "Determining the structures of halogenated marine natural products by total synthesis." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:31737a99-a13c-4110-b36d-1c043b66565b.
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Elatenyne, a brominated C15 acetogenin isolated from the red Laurencia elata marine algae, was originally assigned a pyranopyran structure. Previous total synthesis of the pyranopyran structure has found this assignment to be incorrect. During this work the revised 2,2’-bifuranyl skeleton of elatenyne was suggested, but this skeleton has 32 possible diastereomers. The most likely diastereomer of elatenyne was predicted using computational 13C NMR chemical shift calculation in combination with the possible stereochemical outcomes from the proposed biosynthesis. Chapter 1 introduces the structural misassignment of natural products and describes the misassignment of elatenyne as well as a related chloro enyne. The use of computational methods and biosynthetic postulates to aid structure elucidation are also discussed. Chapter 2 describes the first generation synthesis of cross metathesis coupling partners required for the synthesis of elatenyne from D-mannitol. Chapter 3 describes the completed total synthesis of elatenyne, along with three derivatives and the (E)-isomer of elatenyne; itself a natural product. A comparison of the synthetic data with the isolation data for the natural products is presented, as well as comparison with the synthetic material of Kim and co-workers whose concurrent biomimetic total synthesis is also presented. Chapter 4 describes the modular nature of the devised synthetic route to access any diastereomer of elatenyne and its application to related 2,2’-bifuranyl natural products.
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Lima, Letícia Bazeia. "Triagem da atividade antioxidante e anticolinesterásica de extratos naturais: seleção e estudo químico biomonitorado de Streptomyces sp. e de Psychotria carthagenensis." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-27112011-193019/.
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Esse trabalho descreve o estudo monitorado de extratos de origem microbiológica e vegetal. Com o objetivo de identificar compostos com atividade antioxidante e/ou inibidores da enzima acetilcolinesterase em extratos de origem microbiológica e vegetal do cerrado brasileiro, uma triagem de atividade foi realizada utilizando ensaios simples e rápidos. Nessa triagem dois extratos promissores foram selecionados para os estudos de identificação dos compostos responsáveis pela atividade inicial. O trabalho de purificação foi iniciado com a fração em acetato de etila do extrato etanólico da actinobactéria-36 (50PL), Streptomyces sp., fermentado em meio de canjica amarela que apresentou atividade nos dois ensaios realizados. As atividades antioxidante e anticolinesterásica são relatadas pela primeira vez para essa actinobactéria. Nesse estudo foram identificados dois compostos, o éster metílico do ácido cis-6, cis-8 octadecadienóico e o tetradecanal. Da espécie Psychotria carthagenensis, uma planta da família Rubiaceae, foram objeto de estudo as frações hexânica e acetato de etila oriundas do extrato etanólico das folhas, o extrato hexânico das folhas e o extrato etanólico dos caules. A espécie P. cartahgenensis foi investigada quanto à presença de alcalóides uma vez que é utilizada juntamente com as espécies Psychotria viridis e Banisteriopsis caapi no preparo de uma bebida alucinógena conhecida como ayahuasca. A partir dos extratos etanólicos das sementes, caules e folhas foi realizada uma extração ácido-base resultando em frações ricas em compostos nitrogenados. As frações de alcalóides totais foram analisadas em TLC e revelador específico, o cloro-iodoplatinado, evidenciando a presença de alcalóides. As frações foram analisadas por EM (desreplicação) resultando na identificação de 5 compostos nitrogenados.This work describes the monitored study of extracts from microbiological and plant origin. In order to identify compounds with antioxidant action and/or inhibitors of acetylcholinesterase enzyme in extracts of microbial and plants of the Brazilian Cerrado vegetation, screening for these activities was performed using simple and rapid tests. From this screening, two promising extracts were selected for identification of the compounds responsible for the initially observed activity. Purification was started with the ethyl acetate fraction in the ethanol extract of actinobacteria-36 (50PL), Streptomyces sp., fermented in a yellow hominy culture medium that displayed activity in both tests. Antioxidant and anticholinesterase activities are reported for this actinobacteria for the first time. Two compounds were identified, namely 6(Z),8(Z)-octadecadienoic acid, methyl ester and tetradecanal. The hexane and ethyl acetate fractions of the ethanol extract of the leaves as well as the ethanol extract of the stems from the Psychotria carthagenensis species, a plant of the Rubiaceae family, were studied. This species was investigated for the presence of alkaloids, because it is used together with the species Psychotria viridis and Banisteriopsis caapi in the preparation of a hallucinogenic drink known as ayahuasca. Acid-base extractions of the ethanol extracts of the seeds, stems, and leaves of this plant were carried out, resulting in fractions rich in nitrogen compounds. The total alkaloids fractions were analyzed by TLC and specific revealing with chlorine-iodoplatinate, which evidenced the presence of alkaloids. The fractions were analyzed by MS (derreplication), which allowed for identification of five nitrogen compounds.
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Agostini, Mathieu. "Contribution à l'étude de l'origine naturelle du tramadol et étude phytochimique de deux plantes alpines." Thesis, Université Grenoble Alpes, 2020. http://www.theses.fr/2020GRALV007.
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Cette thèse s’inscrit dans le domaine de la phytochimie et de la pharmacognosie, et comprend deux parties majeures. La première porte sur l’investigation phytochimique des racines de Nauclea latifolia, un arbuste utilisé en médecine traditionnelle pour ses propriétés thérapeutiques. En 2013, la découverte du tramadol, un médicament de synthèse dans les racines de Nauclea latifolia a été exposée à une couverture médiatique inédite. De ce fait, l’origine naturelle du tramadol a été remise en question. L’objectif principal de ce projet est d’isoler du tramadol à partir de nouveaux lots de racines de Nauclea latifolia dans le but de réaliser des analyses isotopiques 14C pour déterminer l’origine naturelle (ou non) du composé.La purification d’extraits de ces racines par HPLC semi-préparative a permis l’isolement de deux échantillons de tramadol. Les analyses isotopiques en carbone 14 des échantillons ont montré des résultats qui tendent à montrer une origine naturelle. Cependant, l’analyse d’un nouvel échantillon de tramadol issu d’un troisième lot est nécessaire pour confirmer/affirmer son origine.Le deuxième volet de cette thèse a porté sur l’étude phytochimique de deux plantes alpines dans le but de valoriser la flore locale en tant que sources de molécules bioactives. La première plante est l’Helianthemum nummularium, une espèce que l’on retrouve en surprésentation dans le régime alimentaire des ongulés montagnards. Afin d’expliquer cette surconsommation, deux hypothèses étaient possibles : 1) valeurs nutritionnelles importantes et 2) consommation de la plante dans un but d’automédication. Dans ce contexte, nous nous sommes principalement intéressés à la deuxième hypothèse en réalisant une analyse phytochimique des parties aériennes de plante. La purification de l’extrait éthanolique des parties aériennes ont permis l’isolement de 8 dérivés polyphénoliques dont certains ont été rapportés comme de potentiels agents antiparasitaires et pourraient présenter un intérêt pour les ongulés. La deuxième plante est le Chenopodium bonus-henricus, une espèce alpine très utilisée dans le secteur alimentaire local. L’étude phytochimique des extraits dichlorométhane et éthanolique des parties aériennes a permis l’isolement de 6 molécules dont une est nouvelle.La valorisation thérapeutique des extraits et molécules issus des plantes alpine, nous a conduit à conduire des tests biologiques. Dans ce contexte, nous nous sommes penchés sur l’induction d’activation du facteur de transcription Nrf2 par les extraits et les molécules isoléesThis PhD. Thesis was carried out in the field of phytochemistry and pharmacognosy, including two major parts. The first part is dedicated to the phytochemical investigation of the roots of Nauclea latifolia, an African shrub largely used in traditional medicine. In 2013, tramadol, a fully synthetic drug was isolated from the roots of Nauclea latifolia. This unpreceded discovery was largely covered by media worldwide As it can be expected, the natural origin of tramadol was inevitably the subject to some discrepancies. The main goal of this project is to isolate tramadol from new samples of N. latifolia in order to perform isotopic 14C analyses to determine the natural origin of compound.The purification of the root extracts by using semi-preparative HPLC led to the isolation of two tramadol. The isotopic 14C analyses of the samples tend to show a natural origin. However, the analysis of a new sample of tramadol from a third batch is necessary to confirm/affirm its origin.The second part of this thesis was dedicated to the phytochemical study of two alpine plants in order to valorize the local flora as a source of bioactive molecules. The first plant was Helianthemum nummularium, which is a specie very present in the alimentary diet of ungulates. In order to explain the preference of ungulates for this species over-consumption, two hypotheses were evoked: 1) nutritional values of the plant, 2) consumption of the plant for self-medication. In this context, we were interested by the second hypothesis by performing a phytochemical analysis of the aerial parts of the plant. The purification of the ethanolic extract allowed to obtain 8 compounds among which some were reported as potential anthelmintic agents.The second plant is Chenopodium bonus-henricus, an alpine specie popular in the local alimentary diet. The phytochemical study of the dichloromethane and ethanolic extracts of the aerial parts led to the isolation of six molecules among which one was never described in any natural resources.Furthermore, the plants of altitude grow in drastic environmental conditions and must develop some defense mechanisms. In this context, the alpine plants extract and the pure molecules were tested on their effect on the activation pathway of Nuclear Factor Erythroid-2-related Factor 2 (Nrf2)
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Rufino, Alessandra Rodrigues. "Emprego de computadores em elucidação estrutural de alcalóides." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/46/46135/tde-25082014-125343/.
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O Sistema Especialista SISTEMAT foi construído com o objetivo de auxiliar os pesquisadores da área de produtos naturais na tarefa de determinação estrutural, estendendo-se também ao químico orgânico sintético. Seus programas aplicativos fornecem propostas de esqueletos fazendo uso dos dados de diversas técnicas espectrométricas, sendo que a espectrometria de ressonância magnética nuclear de 13C tem um papel de destaque entre as demais. Este trabalho descreve a utilização do SISTEMAT como uma ferramenta auxiliar na determinação estrutural de substâncias pertencentes às subclasses dos alcalóides quinolínicos, quinolizidínicos, aporfínicos, benzilisoquinolínicos, isoquinolínicos, pirrolizidínicos, acridônicos e indólicos. Para a realização deste trabalho foi construído um banco de dados contendo 1182 alcalóides, sendo todos coletados da literatura. Nestes 1182 alcalóides, estão presentes 1156 espectros de RMN 13C, 354 espectros de RMN 1H, 320 espectros de massas e as substâncias de origem vegetal estão distribuídos em 49 Famílias, 164 Gêneros e 260 Espécies. Os testes realizados forneceram bons percentuais de acertos para o reconhecimento de esqueletos. Outro programa utilizado neste trabalho foi o de redes neurais artificiais. As redes foram treinadas para auxiliar na determinação estrutural dos alcalóides aporfínicos, fornecendo a probabilidade de uma determinada substância pertencer ao esqueleto pesquisado. Para utilização das redes neurais foi construída uma planilha com os deslocamentos químicos de RMN 13C, de 165 alcalóides aporfínicos, pertencentes a 12 esqueletos diferentes. A rede forneceu ótimos resultados, classificando os esqueletos com alto grau de confiabilidade.The Expert System SISTEMAT was built with the objective of aiding the researchers of the area of natural products in the task of structural determination, also extending to the synthetic organic chemist. Their applications programs supply proposed of skeletons making use of the data of several techniques spectrometrics, and the 13C NMR has a main paper among the others. This work describes the use of SISTEMAT as an auxiliary tool in the structural determination of substances belonging to the underclass of the alkaloids quinoline, quinolizidine, aporphine, benzylisoquinoline, isoquinoline, pyrrolizidine, acridone and indoles. For the accomplishment of this work a database was built containing 1182 alkaloids, being all collected of the literature. In these 1182 alkaloids, are present 1156 spectra of 13C NMR, 354 spectra of RMN 1:00, 320 spectra of masses and the substances of botanical origin are distributed in 49 Families, 164 Genders and 260 Species. They were accomplished around 100 tests, of which 30 are presented in this thesis. These tests supplied good percentile of the successes for the recognition of skeletons. Another program used in this work the one of nets artificial neurais, in which the nets were trained to aid in the structural determination of the aporphine alkaloids was, supplying the probability of a certain substance to belong to the researched skeleton. For use of the nets neurais a spreadsheet was built with the chemical displacements of 13C NMR, of 165 aporphine alkaloids, belonging to 12 different skeletons. The net supplied great results, classifying the skeletons with high reliability degree.
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Ferreira, Marcelo José Pena. "Análise espectral, geração de estrutura e simulação de dados de RMN 13C." Universidade de São Paulo, 2003. http://www.teses.usp.br/teses/disponiveis/46/46135/tde-20032018-142649/.
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O sistema especialista SISTEMAT tem por objetivo auxiliar pesquisadores da área de produtos naturais no processo de determinação estrutural de substâncias. Para tanto, utilizando dados provenientes de várias técnicas espectrométricas e espectroscópicas, principalmente RMN 13C, inúmeros programas foram desenvolvidos com a finalidade de propor o provável esqueleto de uma substância. Essa informação, juntamente com as substruturas apresentadas a partir de um conjunto de dados, é utilizada por geradores estruturais como grandes restrições, a fim de impedir a explosão combinatória e a geração de propostas estruturais incompatíveis com produtos naturais, além de reduzir o elevado tempo computacional gasto durante uma análise. Esse trabalho descreve o desenvolvimento e utilização dos módulos de reconhecimento de esqueletos, determinação e geração estrutural e simulação de dados de RMN 13C de esteróides. Assim, foi elaborada uma base de dados com 1436 substâncias distribuídas entre 119 tipos de esqueletos provenientes das mais diversas fontes naturais. Vários testes foram realizados e bons percentuais de acerto foram obtidos para o reconhecimento de esqueletos e geração de propostas estruturais através da sobreposição dos tipos de anéis encontrados em esqueletos de esteróides. Para validar as propostas estruturais apresentadas pelo gerador, bem como para prever os dados de deslocamentos químicos de novos esteróides, o simulador de dados de RMN 13C foi usado e, quando comparado a um programa comercial de mesma finalidade, apresentou maior exatidão na previsão dos dados.The aim of the expert system SISTEMAT is to aid natural product researchers in the process of structural determination of organic substances. For that, using data from various spectrometric and spectroscopic techniques, mainly 13C NMR, countless programs were developed to propose the most probable skeleton of a substance. This information together with the substructures shown from the data set are utilized by structural generators as important constraints in order to avoid the combinatorial explosion problem and the generation of incompatible structural proposals for natural products, besides reducing the computational time spent during the analysis. This work describes the development and use of the modules of skeleton identification, structural determination and generation, and the 13C NMR data prediction of steroids. Thus, was built a database containing 1436 steroids distributed in 119 different skeletons originated from the most varied natural sources. Several tests were performed, wherein good hit percentuals were obtained for the skeleton identification and structural generation through the overlapping of the types of rings found in the steroid skeletons. For validation of the structural proposals shown by the generator as well as for prediction of the chemical shift data of new substances, the simulator of 13C NMR data was used and next compared with a commercial program of the same purpose, and exhibited higher accuracy in the data prediction.
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Gainche, Maël. "Etudes phytochimiques et activités anti-inflammatoires de plantes médicinales auvergnates." Thesis, Université Clermont Auvergne (2017-2020), 2020. http://www.theses.fr/2020CLFAC001.
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Le projet Plantinauv dans lequel s’inscrivent les travaux de ce mémoire de thèse, a pour but la valorisation du patrimoine botanique d’Auvergne en identifiant des plantes d’intérêts alimentaires et médicinales possédant des activités anti-inflammatoires, et de permettre leur commercialisation (ou celle de leurs bioactifs isolés) sous la forme de produits nutraceutiques, cosmétiques et/ou vétérinaires. Ce projet implique un consortium de partenaires académiques (UMR UNH) et industriels du pôle de compétitivité Vegepolys Valley (Greentech, Domes Pharma, AltoPhyto). Parmi les plantes de la flore auvergnate, seize ont été sélectionnées pour évaluer le potentiel anti-inflammatoire de leurs extraits (tests physico-chimiques et biologiques). Six d’entre elles, présentent sur différentes listes règlementaires (nutraceutique, cosmétique, vétérinaire), ont fait l’objet d’études phytochimiques. Le fractionnement chimio-et bio-guidé de L. sylvatica et D. fullonuma permis d’isoler de nouveaux métabolites secondaires d’intérêt. Quatre nouveaux phénanthrènes présentant des propriétés antiprolifératives prometteuses ont été isolés des parties aériennes de L. sylvatica. La mise en évidence des principaux marqueurs et le dosage de certains d’entre eux ont été réalisés pour les quatre autres plantes (P. erecta, T. angustifolia, H. Stoechas, K arvensis). Enfin, la préparation d’extraits industrialisable à partir de ces plantes a été mise au point dans le but de développer de nouveaux ingrédients commercialisablesThe research work of this thesis, included in the Plantinauv project,aims to enhance the botanical heritage of Auvergne by identifying plants of medicinal and nutritional interest exhibiting anti-inflammatory activities, and to allow their merchandising (or that of their isolated bioactive agents) in the form of nutraceutical, cosmetic and / or veterinary products. This project involves a consortium of academic(UMR, UNH) and industrial partners from the cluster Vegepolys Valley (Greentech, Domes Pharma and Altophyto).Among the plants of the Auvergne flora, sixteen were selected to assess the anti-inflammatory potential of their extracts (chemical and biological tests). Six of them, present on different regulatory lists (nutraceutical, cosmetic, veterinary), have been the subject of phytochemical studies.The chemo-and bio-guided fractionation of L. sylvaticaand D. fullonumextracts allowed the isolation of new secondary metabolites. Four new phenanthrenes with promising anti-proliferative activities on cancer cells were isolated from L. sylvatica. The phytochemical profiles of the four other plants (P. erecta, T. angustifolia, H. stoechas, K arvensis) were also determined. Finally, the standardization of the different plant extracts was studied in order to develop new marketable ingredients
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Li, Guoqiang. "Structure elucidation of bioactive natural products." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0004/NQ29469.pdf.
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Murphy, Annabel Christine. "Structure Elucidation and Synthesis of Natural Products." Thesis, University of Canterbury. Chemistry, 2008. http://hdl.handle.net/10092/1748.
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In this thesis, synthetic chemistry was used as a tool in the exploration of various aspects of natural products discovered by the natural products research group at the University of Canterbury. Work on the constituent amino acids and connectivity of the pteratides, a potently cytotoxic series of cyclodepsipeptides, had been completed before the beginning of this work (carried out by Miss C. Chen). The elucidation of the stereochemistry of the constituent amino acids was undertaken in this present work. The synthesis of all stereochemical entities of a number of unusual amino acids, which were either not available commercially or were expensive, was carried out, providing reference materials for comparison to the natural products. The synthesis of the diastereoisomers of one of these amino acids, 4-methylproline, was carried out by modification of literature procedures, which led to the development of an improved, concise and stereoselective synthesis. The hydrolysis of the natural products, derivatisation of the resultant hydrolysates, synthetic and commercial reference amino acids and HPLC analysis allowed the full stereochemical assignment of the pteratide series. The total synthesis of spiro-mamakone A, a cytotoxic polyketide isolated by Dr S. van der Sar, was undertaken. The synthesis was not successfully completed due to difficulties in the late-stage formation of a crucial enedione motif. However, very advanced intermediates were successfully synthesised. These synthetic analogues of the natural product were analysed for biological activity, allowing valuable insight into the structure-activity relationship, for example, demonstrating the importance of the enedione moiety to biological activity.
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施麗琼 and Lai-king Sy. "Structure elucidation and oxidation chemistry of natural products." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1998. http://hub.hku.hk/bib/B3123768X.
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Sy, Lai-king. "Structure elucidation and oxidation chemistry of natural products /." Hong Kong : University of Hong Kong, 1998. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19737300.
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Daoust, Julie. "Isolation and structure elucidation of bioactive marine natural products." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/37536.
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Clionamines A-D (2.6-2.9) are new aminosteroids isolated from South African specimens of the sponge Cliona celata. All four compounds (2.6-2.9) are activators of autophagy in MCF-7 cells. Autophagy is a catabolic process that plays an important role in maintaining cellular homeostasis. Autophagy is also directly involved in the removal of bacterial and viral antigens and in the development of cancerous tumors.
The novel sesterterpenoid ansellone A (3.4) was isolated from the nudibranch Cadlina luteomarginata and was later found to have been sequestered by the nudibranch from the sponge Phorbas sp. Ansellone A (3.4) is an activator of the cAMP signalling pathway. Following the isolation of 3.4, the novel sesterterpenoids ansellones B-D (4.3-4.5) as well as alotaketal E (4.6) were isolated from the sponge Phorbas sp. and were found to also be activators of the cAMP signalling pathway.
Several bacterial isolates were obtained from the sponge Phorbas sp. in order to investigate the possibility that the ansellones and the alotaketals isolated from this sponge were biosynthesized by a bacterial symbiont. Since these sesterterpenoids were activators of the cAMP signalling pathway, the investigation was conducted using bioassay guided fractionation of the bacterial isolates. The new meroterpenoid phorbasolic acid (5.1) was isolated, but no sesterterpenoids were found in the bacterial isolates.
In an effort to identify molecules with antibiotic properties, a biological assay was designed to screen for inhibitors of the citrate synthase type II enzyme. One aspect of this enzyme that is of therapeutic interest is that Gram-negative bacteria possess a very different isoform of the enzyme than Gram-positive bacteria and eukaryotes. Therefore, an antibiotic specific to type II citrate synthase would target Gram-negative bacteria selectively. An extract from a culture of Bacillus pumillus inhibited the enzyme in the assay. Although the molecule responsible for this effect has yet to be identified, the new aliphatic amide 12-methyl tridecanamide (6.1) was isolated.
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Reddy, Priyanka, and saipriyanka@gmail com. "Studies in Marine Natural Products." RMIT University. Applied Sciencez, 2009. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20091023.091658.
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The focus of this thesis was to study the chemotaxonomic relationship of selected southern Australian marine brown algae of the genera Cystophora and Sargassum. Consequently, this resulted in the isolation and structure elucidation of six new terpenoids from two southern Australian marine brown algae Cystophora moniliformis and Sargassum fallax together with 10 previously reported natural products. As a result of the re-isolation of these known secondary metabolites, updated and complete structural characterisation data could be provided for the first time for 7 of these compounds. Chemotaxonomic studies of Cystophora moniliformis resulted in the isolation of two new cyclic epimeric terpene diols moniliforminol A (3.25) and moniliforminol B (3.26), a new linear farnesyl acetone derivative (3.27) and the previously described terpenoids (3.19)-(3.24). This study also resulted in the first complete 2D NMR characterisation for compounds (3.21) to (3.24) as well as the first report of (3.24) occurring as a natural product. All structures were elucidated by detailed spectroscopic analysis with the relative configurations of (3.25) and (3.26) being established by selective 1D nOe NMR experiments. The proposed biosynthetic pathway for the above compounds has also been described. Chemical investigation of the Southern Australian marine brown alga Sargassum fallax resulted in the isolation of three new meroditerpenoids fallahydroquinone (4.8), fallaquinone (4.9) and fallachromenoic acid (4.10), together with the previously reported compounds sargaquinone (4.1) (isolated and identified in a mixture with sargaquinoic acid), sargahydroquinoic acid (4.2), sargaquinoic acid (4.3) and sargachromenol (4.11). As a result of this study the complete 2D NMR characterisation for sargahydroquinoic acid (4.2) and sargaquinoic acid (4.3) could also be reported for the first time. All structures were elucidated by detailed spectroscopic analysis. Sargahydroquinoic acid (4.2) and sargaquinoic acid (4.3) displayed moderate antitumour activity.
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Forestieri, Roberto. "Isolation, structure elucidation, and total synthesis of bioactive natural products." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/45668.
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Su, Qingxi. "Isolation and Structure Elucidation of Anticancer and Antimalarial Natural Products." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/72954.
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As part of an International Cooperative Biodiversity Group (ICBG) program and a collaborative research project with the Natural Products Discovery Institute, twenty plant extracts were investigated for their antiproliferative and antimalarial activities. Bioassay guided fractionation of thirteen extracts led to the identification of three new antiproliferative compounds, ethyl leptaulosides A-C (5.1-5.3), six new antiplasmodial compounds, apoplanesiacarpan A and B (2.4-2.5), (±)-rhodomyrtosone F (3.1), (±)-calliviminone C (3.2), 3α-angeloyloxy-15-hydroxylabda-7,13-dien-16,15-olid-18-oic acid (4.1), 3α-angeloyloxy-15-methoxylabda-7,13-dien-16,15-olid-18-oic acid (4.2), and twenty-six known compounds. The structures of these compounds were elucidated by using a combination of 1D (1H and 13C) and 2D NMR spectroscopy, mass spectrometry, UV, IR, CD, optical rotation, and chemical modifications. Compounds 5.1 and 5.2 showed moderate antiproliferative activity against the A2780 human ovarian cancer cell line assay with IC50 values of 3 uM and 10 uM, respectively. Compound 3.1 showed potent antiplasmodial activity with an IC50 value of 100 nM, while compounds 3.2 and 4.1 showed moderate antiplasmodial activity with IC50 values of 4 uM and 10 uM, respectively. The other compounds had IC50 values larger than 20 ug/mL, and were thus either inactive or only weakly active.Ph. D.
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Liu, Yixi. "Isolation and Structure Elucidation of Anticancer and Antimalarial Natural Products." Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/52259.
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As part of an International Cooperative Biodiversity Group (ICBG) program and a continuing search for antiproliferative natural products from the Madagascar rainforest, and a collaborative research project established between Virginia Tech and the Institute for Hepatitis and Virus Research (IHVR) focusing on searching for bioactive natural products from tropical forests in South Africa, 20 extracts were selected for investigation based on their antiproliferative activities against A2780 human ovarian cancer cell line or antimalarial activities against the Dd2 strain of Plasmodium falciparum. Bioassay-guided fractionation of seven of the extracts yielded twenty new compounds and twenty-four known compounds, and their structures were elucidated by using a combination of 1D (1H and 13C) and 2D NMR spectroscopy including COSY, HASQC, HMQC, HMBC, and NOESY sequences, mass spectrometry, UV, IR, ECD, optical rotation, and chemical conversions. In addition, ten known compounds were isolated from another five of the extracts, while studies on the remaining extracts were suspended due to loss of activity, unworkable small amounts of material, or low structural interest.
The plants and their metabolites are discussed in the following order: five new antimalarial 5,6-dihydro-𝛼-pyrones and six bicyclic tetrahydro-𝛼-pyrone derivatives from Cryptocarya rigidifolia (Lauraceae); two new and five known antiproliferative lignans from Cleistanthus boivinianus (Phyllanthaceae); two new and two known antiproliferative sesquiterpenes lactones from Piptocoma antillana (Asteraceae); one new antiproliferative 1,4-naphthoquinone, one known antiproliferative isoflovonoid, and five known antiproliferative stilbenoids from Stuhlmannia moavi (Leguminosae); four known antiproliferative bisbenzylisoquinoline alkaloids from Anisocycla grandidieri (Menispermaceae); one new and two known antiproliferative butanolides, and two new antiproliferative secobutanolides from Ocotea macrocarpa (Lauraceae); one new antiproliferative and five known antiproliferative diterpenoids from Malleastrum rakotozafyi (Meliceae); and 10 known compounds from Monoporus sp. (Myrsinaceae), Premna corymbosa (Verbenaceae), Premna perplexanes (Verbenaceae), Epallage longipes (Asteraceae), and Cinnamosma fragrans (Canellaceae).Ph. D.
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Murphy, Brian Thacher. "Isolation and Structure Elucidation of Antiproliferative Natural Products from Madagascar." Diss., Virginia Tech, 2007. http://hdl.handle.net/10919/29599.
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As part of an ongoing search for bioactive natural products from the endemic rainforests and surrounding ocean in Madagascar, a total of four extracts were comprehensively studied and were found to contain novel and/or bioactive compounds. The following dissertation discusses the isolation, structure elucidation, and bioactivity studies of these isolates.
The following compounds from plants of Madagascar's rainforest are discussed in the order they were studied: flavonoids and long-chain compounds from Schizolaena hystrix, a cyclohexene derivative and butenolides from Artabotrys madagascariensis, and limonoids from Malleastrum sp. From the Malagasy marine ascidian Trididemnum sp. collected in the Indian Ocean, the identification as well as the potential biosynthetic origin of polyketide derived bistramides is reported.
n an attempt to explore other facets of natural products chemistry, the second part of this dissertation discusses the process of designing potential anticancer agents based on the scaffold of a natural product. The biomolecular target of these studies is an enzyme that is overexpressed in tumor cells, namely Cdc25B, whose inhibition catalyzes cell cycle arrest at the G2/M transition of the cell cycle. Several analogs of a potent Cdc25B inhibitor were synthesized and tested in the enzyme-based assay.Ph. D.
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Davis, Andrew Stewart. "Attempts to find the correct structure of uniflorine A." School of Chemistry - Faculty of Science, 2008. http://ro.uow.edu.au/theses/143.
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The alkaloid uniflorine A was isolated in 2000 from the leaves of the tree Eugenia uniflora L, together with two other water soluble alkaloids, uniflorine B and the known alkaloid (+)-(3α,4α,5β)-1-methylpiperidine-3,4,5-triol piperidine. Uniflorine A was found to be an inhibitor of the α-glucosidases, rat intestinal maltase and sucrase, with IC50 values of 12 and 3.1 μM, respectively, and its structure was deduced from NMR analysis to be structure 1. Uniflorine B was also found to be an inhibitor of the above α-glucosidases and its structure was determined from NMR analysis to be structure 2. The initial goal of this study was to complete the total synthesis of 1 and determine the validity of its proposed structure. In the event, an efficient 9-step diastereoselective synthesis of 1 was achieved by using the Petasis borono-Mannich reaction, ring-closing metathesis and stereoselective cis-dihydroxylation as key steps. The structure of our synthetic 1 was unequivocally established by a single-crystal X-ray crystallographic study of its pentaacetate derivative. However, the 1H and 13C NMR data for synthetic 1 did not match with those reported for uniflorine A; the latter showed many more downfield peaks in the 1H NMR, perhaps consistent with the amine salt. The 1H NMR of the hydrochloride salt of synthetic 1, however, did not match the literature spectroscopic data either. We therefore concluded that the structure assigned to uniflorine A was not correct. We also found that the coupling constant J1,8a of 4.5 Hz for uniflorine A, was more consistent with the relative syn-H-8a, H-1 configuration, suggesting that uniflorine A, if it was an indolizidine alkaloid, had the same H-1 configuration as castanospermine. Our attempts to prepare 2-epi-1 and 1,2-di-epi-1 were unsuccessful due to unexpected competing side-reactions. In addition, the diasteresoselective synthesis of the C-1, C-2 di-epimer of 1 was achieved. This synthesis employed a novel pyrrolo[1,2-c]oxazin-1-one precursor to allow for the reversal of π-facial diastereoselectivity in an osmium(VIII)-catalysed syn-dihydroxylation (DH) reaction. The NMR spectroscopic data of this epimeric compound and that of related isomers did not match that of the natural product. From a comparison of the NMR data of uniflorine A and uniflorine B with that of casuarine and the known synthetic 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine isomers we concluded unequivocally that uniflorine B is the known alkaloid casuarine. Although we cannot unequivocally prove the structure of uniflorine A, without access to the original material and data, the published data suggest that the natural product is also a 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine with the same relative C-7-C-7a-C-1-C-2-C-3 configuration as casuarine. We thus suggest that uniflorine A is 6-epi-casuarine.
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Heaviside, Elizabeth Anne. "Analogues of antibacterial natural products." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:6b5bd771-515b-49d0-8ec9-cee115d3aebf.
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Analogues of Antibacterial Natural Products Elizabeth Anne Heaviside, St Catherine’s College, University of Oxford DPhil Thesis, Trinity Term 2012 This thesis is concerned with the synthesis and biological evaluation of structural mimics for the natural products 16-methyloxazolomycin and lemonomycin which display potent biological activity including antibacterial and antitumour activity. Chapter 1 explores methods and approaches to the discovery of new antibacterial drugs and the challenges faced in this respect. It also gives an overview of the properties of the natural products investigated in the following chapters and summarises previous synthetic approaches to these molecules published in the scientific literature. Chapter 2 describes the work carried out towards the synthesis of the diazabicyclo[3.2.1]octane unit of the tetrahydroisoquinoline antitumour antibiotic lemonomycin. The intended retrosynthesis of the natural product led to a 2,5-disubstituted pyrrolidine bearing a 1ʹ-amino functional group; a series of routes were explored for the synthesis of this unit. Using (S)-pyroglutamic acid, strategies using Eschenmoser and thiolactim ether coupling reactions were investigated. A sequence based on the formation of a pyrrolidine ring from the cyclisation of an appropriately substituted oxime ether derived from L-phenylalanine was then implemented but a competing Beckmann rearrangement/Grob fragmentation prevented access to the desired heterocycle. Preliminary investigations were also carried out on the modification of cyclic imines derived from oxime ethers which did not undergo Beckmann rearrangement. Chapter 3 describes the synthesis of a library of densely functionalised tetramic acid and pyroglutamate mimics for the right-hand fragment of 16-methyloxazolomycin, and their coupling with a gem-dimethylamide unit mimicking the middle fragment of the natural product. Tetramates were accessed through the Dieckmann cyclisation of N-acyloxazolidines and were derivatised with various alkyl halides. The pyroglutamates were accessed via the highly diastereoselective aldol cyclisation of N-acyloxazolidines formed by the amide coupling of a threonine derived oxazolidine and β-keto-acids. A series of β-keto-acids were synthesised through the acylation and subsequent ring-opening/decarboxylation reaction of Meldrum’s acid. The formation of right-hand/middle fragment adducts was explored using cycloaddition, alkylation and Sonogashira chemistry before a Wittig protocol led to the formation of adducts (E)- and (Z)- 402 and 403. Biological evaluation of the compounds synthesised in this chapter was carried out using both broth and hole-plate bioassays and active compounds were identified. Of particular note was that the Wittig adducts displayed a higher level of activity against Gram-negative E. coli than either the pyroglutamate or amide motifs alone.
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Maoela, Manki Sarah. "Spectroelectrochemical determination of the antioxidant properties of carpobrotus mellei and carpobrotus quadrifidus natural products." Thesis, University of the Western Cape, 2009. http://hdl.handle.net/11394/3299.
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Philosophiae Doctor - PhDSouth African Carpobrotus species have been found to contain hydrolysable tannins,various flavonoids e.g. rutin and hyperoside, phytosterols and aromatic acids which have a diverse range of pharmacological properties including antimicrobial and, antioxidant activities. The main aim of the thesis was to determine the natural products in C. mellei and C. quadrifidus using chromatographic techniques and electrochemical analysis. The antioxidant activity of both Carpobrotus species was determined by using a superoxide dismutase (SOD) biosensor. ESI-LC-MS was used to separate and determine flavonoids in C. mellei and C. quadrifidus. 8 flavonoid compounds: catechin, epicatechin, epicatechin-epicatechin, coumarylquinic acid, isorhamnetin, quercetin-hexose (hyperoside), rutin and myricetin-deoxyhexose were identified. Cyclic and square wave voltammetry were used to detect flavonoids from C. mellei and C. quadrifidus. Catechin was detected in the ethyl acetate extract of C. mellei and C. quadrifidus. The oxidation potential of the plant extracts were observed at +150.6 mV to +1072.6 mV. The oxidation mechanism proceeds in sequential steps, related to the catechol moiety, -OH groups in C ring and the resorcinol group. The oxidation process of the catechol moiety involves a two electron - two proton reversible reaction and forms o-quinone. This occurs first at low potential and is a reversible reaction. The hydroxyl group in the C ring and resorcinol group oxidise there after and undergo an irreversible reaction. UV-vis and FTIR spectroscopy were used to confirm the presence of catechin in the ethyl acetate extract of both plants.UV-visible spectroelectrochemistry confirmed the oxidation process of catechin at constant potential. Since C. mellei and C. quadrifidus were confirmed to contain flavonoids by ESI-LC-MS and electrochemical analysis, the antioxidant activity was further investigated using a SOD biosensor. The superoxide dismutase (SOD) enzyme was immobilised with 1% Nafion on a platinum electrode. Detection limit and sensitivity of the SOD biosensor were found to be 0.03918 μmol L-1 and 1.44 μA(μmol L-1)-1, respectively. The results showed that C. mellei and C. quadrifidus have antioxidant activity, with relative antioxidant capacity (RAC) of 24% and 42%, respectively. May 2009
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Carr, Gavin. "Bioactive marine natural products : isolation, structure elucidation and synthesis of pharmacophore analogues." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/23166.
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Bioassay-guided fractionation of the marine sponge Spongia irregularis led to the isolation of a new sulfated sesterterpenoid, irregularasulfate (2.16), along with two known sulfated sesterterpenoids, halisulfate 7 (2.14) and hipposulfate C (2.15). All three compounds (2.14-2.16) inhibit the related phosphatases calcineurin, PP1 and PP2A. The analogue 2.23 was synthesized and showed similar phosphatase inhibitory activity to the natural products. One new bafilomycin analogue, bafilomycin F (3.2), along with three known bafilomycin analogues, bafilomycin A1 (3.1), bafilomycin B1 (3.3) and bafilomycin D (3.4), were isolated from a marine-derived bacterium identified as Streptomyces sp. All four compounds (3.1-3.4) are extremely potent inhibitors of autophagy. Indoleamine 2,3-dioxygenase (IDO) is a relatively new and promising cancer drug target. Synthetic analogues of exiguamine A, the most potent IDO inhibitor reported to date, were prepared and evaluated for their ability to inhibit IDO in vitro and in vivo. The most potent of these analogues (4.32, 4.38, 4.39, 4.43 and 4.52) inhibit IDO in vitro with potency comparable to exiguamine A. A new exiguamine analogue, exiguamine C (5.2), was isolated from the crude extract of Neopetrosia exigua. Exiguamine B (5.1) was also isolated from this crude extract in order to confirm the structure, and the relative configuration was determined with the aid of synthetic exiguamine B. Bioassay-guided fractionation of the marine fungus Plectosphaerella cucumerina led to the isolation of three new alkaloids, plectosphaeroic acids A-C (6.1-6.3). All three compounds inhibit IDO with approximately the same potency, while the related compound T988 A was completely inactive. Cinnabarinic acid was synthesized in order to aid with the structure elucidation of plectosphaeroic acids A-C. Cinnabarinic acid and analogues were also active against IDO and represent a new pharmacophore for IDO inhibition. The depsipeptides turnagainolide A (7.3) and turnagainolide B (7.4) were isolated from Bacillus sp. Both of these compounds activate the enzyme SHIP1 in vitro. Total syntheses of turnagainolides A and B were accomplished using solid-phase peptide synthesis, and comparison of the synthetic material with the natural products confirmed their structures. Two novel compounds, the peptide 8.1 and the carotenoid 8.7, were isolated from two unidentified marine sponges. The structure of 8.1 was confirmed by a total synthesis using solid-phase peptide synthesis. Analogues of 8.1 were also prepared and showed moderate cytotoxicty against T98G cancer cells.
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Ashour, Mohamed A. A. "Structure elucidation of bioactive marine natural products using modern methods of spectroscopy." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=982523963.
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Ahmad, Mansoor. "Investigations into the isolation, structure elucidation and biosynthesis of bioactive natural products." Thesis, University of Warwick, 2011. http://wrap.warwick.ac.uk/43414/.
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This project is divided into two parts. The first part of the project involved the investigation of fish toxins produced by Streptomyces species. Samples for fishexposure experiments were prepared from an actinomycete belonging to the S. griseus clade isolated from a site of major fish kills, as well as from the type strain, Streptomyces griseus DSM 40236. Fish-exposure samples were prepared through a series of consecutive HPLC separations. We were able to narrow down the highest level of fish toxicity to four fractions, each containing only a handful of compounds. Comparison of the metabolic profile of the most toxic fractions showed that many of the compounds were common to all of them e.g. compounds yielding ions with m/z = 213, 241, 239, 301 and 309 were present in all the fractions. Some of these compounds were purified and analysed by high resolution mass spectrometry to determine their molecular formulae. A sample preparation and purification protocol for the fish toxins has been developed in this work. It was shown that the S. griseus type strain produces ichthyotoxic metabolites in addition to the environmental strain. This is a novel and unexpected observation. The second part of the project involved structural and biosynthetic investigations of the iron-chelator and natural Angiotensin Converting Enzyme (ACE) inhibitor foroxymithine. The high structural similarity of foroxymithine to the known siderophore coelichelin and the lack of unambiguous experimental evidence in the literature to support the proposed structure of foroxymithine provided the impetus for these investigations. Foroxymithine was purified from a novel source, the culture supernatant of Streptomyces narbonensis. The gallium complex of purified foroxymithine was prepared and analysed by one- and two-dimensional high-field NMR experiments (1H, COSY, HSQC, HMBC, NOESY, TOCSY and Difference NOE), which allowed the 1H and 13C NMR signals for the complex to be assigned. Careful inspection of the 1H NMR spectrum of Ga-foroxymithine revealed two signals (a major and a minor) for several of the protons. The origin of these signals was investigated using variable temperature and 71Ga NMR experiments, and by LC-MS analyses on a homochiral stationary phase. The duplicate signals were proposed to be associated with the existence of conformational isomers of Ga-foroxymithine. The absolute stereochemistry of the four amino acid constituents of Ga-foroxymithine was determined using Marfey’s method. Authentic standards of two of the anticipated acid-hydrolysis products of Ga-foroxymithine, D- and L-N5-hydroxyornithine were chemically synthesized to facilitate the Marfey’s analysis. The results confirmed that foroxymithine contains L-N5-hydroxyornithine. Similar analysis was performed using the authentic standards of D- and L-serine and the results confirmed that foroxymithine contains L-serine. Marfey’s method was also applied to elucidate the absolute stereochemistry (previously unknown) of coelichelin. Fe-coelichelin was purified from Streptomyces coelicolor M145. Marfey’s derivatised coelichelin hydrolysate and Marfey’s derivatives of L-Thr, L-allo-Thr, D-allo-Thr were analyed. The results showed that coelichelin contains D-allo-Thr. Similarly, analyses were carried out using the Marfey’s derivatives of chemically synthesised D- and L-N5- hydroxyornithine, however the results were inconclusive. The biosynthesis of foroxymithine in S. narbonensis was also investigated. A gene fragment proposed to be within the putative foroxymithine biosynthetic gene cluster was amplified by PCR from the genomic DNA of S. narbonensis. The gene fragment was cloned into a plasmid vector and sequenced. This confirmed that it encodes part of a putative formyl transferase that could be involved in foroxymithine biosynthesis. Fosmid libraries of S. narbonensis genomic DNA were prepared. Despite exhaustive efforts, a fosmid clone containing the putative formyl transferase encoding gene fragment could not be identified via PCR based screening of the library.
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Williams, Russell Brian. "Isolation and Structure Elucidation of Cytotoxic Natural Products from Suriname and Madagascar." Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/45831.
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Through a continuing search for anticancer compounds as part of an International
Cooperative Biodiversity Grant program, the extracts of two plants were selected for study
on the basis of their cytotoxic activity. These extracts were further fractionated to yield
four compounds. The structures of these compounds were elucidated with mass
spectrometry and 1-D and 2-D NMR spectroscopy.
The ethyl acetate extract of the twigs of Garcinia macrophylla from Suriname was
weakly cytotoxic in the A2780 human ovarian cancer cell bioassay. The known
benzophenone guttiferone A and a new guttiferone analog, named guttiferone G, were
isolated from the extract and found to be responsible for the bioactivity. A known
triterpene, friedelin, was also isolated from the extract and found to be inactive. The
structure of guttiferone A was determined by comparison of its NMR data to those found in
the literature. The structure of guttiferone G was determined by comparison to guttiferone
A and through careful examination of both 1D and 2D NMR data.
An extract of Bridelia tulasneana from Madagascar yielded one compound. It was
identified as the known lignan deoxypodophyllotoxin and was responsible for the
bioactivity. It was identified by a comparison of its spectral data to those found in the
literature and those of an authentic sample.Master of Science
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Wang, Ming. "Isolation and Structure Elucidation of Antiproliferative and Antiplasmodial Natural Products from Plants." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/73742.
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As part of an International Cooperative Biodiversity Group (ICBG) program and a collaborative research project with the Natural Products Discovery Institute, four plant extracts were investigated for their antiproliferative and antiplasmodial activities. With the guidance of bioassay guided fractionation, two known antiproliferative terpenoids (2.1 and 2.2) were isolated from Hypoestes sp. (Acanthaceae), four known antiplasmodial liminoids (3.1-3.4) were isolated from Carapa guianensis (Meliaceae), one inactive terpenoid (4.1) was isolated from Erica maesta (Ericaceae), and four cerebrosides (4.2-4.5) were obtained from Hohenbergia antillana (Bromeliaceae).
The structures of these compounds were elucidated by using 1D (1H and 13C), 2D (HMBC, HSQC, COSY, NOESY) NMR spectroscopy and mass spectrometry. The structures of the compounds were also confirmed by comparing them with reported values from the literature.
Compounds 2.1 and 2.2 showed moderate antiproliferative activity against the A2780 human ovarian cancer cell line with IC50 values of 6.9 uM and 3.4 uM, respectively. They also exhibited moderate antiplasmodial activity against chloroquine-resistant Plasmodium falciparum strain Dd2 with IC50 values of 9.9 ± 1.4 uM and 2.8 ± 0.7 uM, respectively. Compounds 3.1 to 3.4 had moderate antiplasmodial activity against Plasmodium falciparum Dd2 strain with IC50 values of 2.0 ± 0.3 uM, 2.1 ± 0.1 uM, 2.1 ± 0.2 uM and 2.8 ± 0.2 uM, respectively. Compounds 4.1 and 4.2 showed very weak antiplasmodial activity against Plasmodium falciparum Dd2 strain, with IC50 values between 5 and 10 ug/mL.Master of Science
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Hauler, Carolin [Verfasser]. "Identification and determination of N-methylpyrrole-containing halogenated natural products in marine samples / Carolin Hauler." München : Verlag Dr. Hut, 2019. http://d-nb.info/119428888X/34.
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Presley, Christopher Charles. "Isolation, Structure Elucidation, and Total Synthesis of Biologically Active Natural Products from Plants." Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/79978.
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As a part of the continuing search for bioactive compounds with the Madagascar International Cooperative Biodiversity Group (ICBG), and in collaboration with the Natural Products Discovery Institute of the Institute for Hepatitis and Virus Research (IHVR), thirteen plant extracts were investigated for antiplasmodial activity, thirteen plant extracts were investigated for antiproliferative activity, and one extract was investigated for inhibitors of the shikimate pathway in Plasmodium falciparum. Bioassay-guided fractionation of the extracts led to the identification of nineteen compounds with both antiplasmodial and antiproliferative activity, and thirteen compounds with only antiproliferative activity. Thirteen of these compounds (2.1 – 2.9, 3.3, 3.4, 4.5, and 5.1) were previously unknown. In addition total synthesis was used to confirm the structure of one new compound (4.5) and two other new natural-product like compounds (4.6 and 4.7) were also synthesized and investigated for antiplasmodial activity.Ph. D.
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Kawame, Naoyuki. "X-ray analysis of a new super-structure of natural mordenite and structure determination of two synthetic crystals." Kyoto University, 2007. http://hdl.handle.net/2433/136429.
Full textAbstract:
Kyoto University (京都大学)0048
新制・課程博士
博士(人間・環境学)
甲第13156号
人博第363号
新制||人||89(附属図書館)
18||D||164(吉田南総合図書館)
UT51-2007-H429
京都大学大学院人間・環境学研究科文化・地域環境学
(主査)教授 玉田 攻, 教授 田村 類, 教授 阪上 雅昭
学位規則第4条第1項該当
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Yoder, Brent Jason. "Isolation and Structure Elucidation of Cytotoxic Natural Products from the Rainforests of Madagascar and Suriname." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/29756.
Full textAbstract:
As part of an ongoing investigation of new bioactive metabolites from rainforest flora, extracts from five different plants were determined to have interesting compounds that were new and/or cytotoxic. These phytochemicals were isolated by various separation techniques and then characterized by common spectroscopic methods.
A bark extract of a Tambourissa species yielded a new hydroxybutanolide with moderate cytotoxicity. The long hydrocarbon chain in this molecule is unique, and its structure was determined by various NMR techniques.
A fruit extract from Macaranga alnifolia yielded four new prenylated stilbenes, one new geranylated dihydroflavanol, and five known compounds. The stilbenoids are highly cytotoxic, and the National Cancer Institute (NCI) further evaluated one of the new compounds.
Bark and leaf extracts from Cerbera manghas yielded a known iridoid and a known cardiac glycoside, both of which showed good bioactivity. The cytotoxicity associated with the iridoid is unprecedented, and it also was further evaluated by the NCI.
An extract of a Cordia species yielded two known compounds - a naphthoquinone dimer and a triterpene. Both of these structures are new to the Cordia genus of plants and showed moderate bioactivity.
An extract of a Monoporus species yielded a known triterpene saponin. The compound has been previously located in the same plant family, but it is new to this genus and has no prior record of cytotoxicity.Ph. D.
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Dai, Yumin. "Isolation, Synthesis and Structure-Activity Relationship Study of Anticancer and Antimalarial Agents from Natural Products." Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/24193.
Full textAbstract:
The Kingston group's engagement in an International Cooperative Biodiversity Group (ICBG) program and a collaborative research project established between Virginia Tech and the Institute for Hepatitis and Virus Research (IHVR) has focused on the search for bioactive natural products from tropical forests in both Madagascar and South Africa. As a part of this research, a total of four antiproliferative extracts were studied, leading to the isolation of fourteen novel compounds with antiproliferative activity against the A2780 human ovarian cancer line. One extract with
antimalarial activity was studied, which led to the isolation of two new natural products with antiplasmodial activity against a drug-resistant Dd2 strain of Plasmodium falciparum.
The plants and their secondary metabolites are discussed in the following order: two new antiproliferative acetogenins from a Uvaria sp. (Annonaceae); two new antiproliferative calamenene-type sesquiterpenoids from Sterculia tavia (Malvaceae); two new antiproliferative triterpene saponins from Nematostylis anthophylla (Rubiaceae); six new antiproliferative homoisoflavonoids and two new bufatrienolides from Urginea depressa (Asparagaceae); and two
new antiplasmodial anthraquinones from Kniphofia ensifolia (Asphodelaceae).
The structures of all these compounds were determined by analysis of their mass spectrometric, 1D and 2D NMR, UV and IR spectroscopic and optical rotation data. Other than structural elucidation, this work also involved bioactivity evaluations of all the isolates, as well as total synthesis of the two antiproliferative sesquiterpenoids, and a structure-activity relationship (SAR) studies on the antiplasmodial anthroquinones.Ph. D.
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Ratnayake, Anokha Sayani. "Structure elucidation of natural products from endophytic fungi and higher plants and total synthesis of microcarpalide." Thesis, University of Hawaii at Manoa, 2003. http://hdl.handle.net/10125/6907.
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Barra, Lena [Verfasser]. "Studies on the Biosynthesis and Structure Elucidation of Terpene Natural Products by Isotopic Labeling Experiments / Lena Barra." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/1177881667/34.
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Ragubeer, Nasheen. "Evaluation and application of electroanalysis for the determination of antioxidants." Thesis, Rhodes University, 2007. http://hdl.handle.net/10962/d1003981.
Full textAbstract:
The role of antioxidants in the prevention of neurodegenerative diseases has been well documented. The use of synthetic antioxidants has decreased due to the ssociation of these compounds with certain cancers. Thus, the search for novel natural antioxidants has gained much focus in research. Most common methods of determining antioxidant capacity are the radical generated assays and biological assays such as lipid peroxidation and the nitroblue tetrazolium assay. Electrochemical methods have been proposed for the determination of bio-active compounds such as antioxidants. The electrochemical methods of cyclic voltammetry and square wave voltammetry were evaluated for the determination of antioxidant capacity initially examining known antioxidants and then using plant extracts of Sutherlandia frutescens as a case study. The antioxidant properties determined by electrochemical methods were validated utilising the non-biological methods of the DPPH, TEAC, ferrozine and FC assay and biological pharmacological methods. The results indicated that Sutherlandia frutescens contains potent antioxidant compounds that are able to reduce lipid peroxidation. The electrochemical techniques of square wave voltammetry and cyclic voltammetry were applied for the screening of a large number of extracts of various algae for the detection of antioxidant compounds. The results indicated that electrochemistry can be used as a preliminary method for the rapid screening of a large number of crude samples for antioxidant compounds. Electrochemical methods were also evaluated as a method for guiding the isolation and purification of antioxidant metabolites in Sargassum elegans. Solvent partitioning and fractionation of the marine alga allowed for the purification of antioxidant compounds. At each step of purification electrochemical methods were utilized to determine which fractions contained the more potent antioxidant compounds and thus guide further purification. The purified antioxidant compounds were elucidated using NMR to determine the structure of the antioxidant compounds.
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Mould, Katy M. "Studies towards the total synthesis and structure elucidation of leiodolide A." Thesis, University of St Andrews, 2013. http://hdl.handle.net/10023/4113.
Full textAbstract:
Leiodolide A is a unique natural product isolated from Pacific marine sponges which has provided an interesting target for total synthesis due to its complex structure and undefined stereochemistry. Although synthetic work towards the synthesis of sister compound leiodolide B has been published, the total synthesis of leiodolide A is yet to be achieved but remains an important target due to high potency against leukaemia, non-small lung and ovarian cancers. The convergent strategy towards the synthesis of leiodolide A involved the synthesis of three subunits; a synthetic route to the C21-C25 vinyl stannane is described, and efforts towards the synthesis of the bidirectional C11-C20 subunit are detailed. Asymmetric vinylogous aldol methodology was developed for the installation of the 1,2-syn propionate motif found in the C1-C10 subunit and in other polypropionate natural products, and was shown to be applicable to a range of substrates in moderate diastereoselectivity and excellent enantioselectivity.
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Karkare, Sampada S. "Isolation and Structure Elucidation of Antiproliferative Agents From Madagascar Rainforests." Thesis, Virginia Tech, 2007. http://hdl.handle.net/10919/34945.
Full textAbstract:
Through our continuing search for anticancer agents from Madagascar rainforests as a part of International Cooperative Biodiversity Group (ICBG), we received two extracts which were active against the A2780 human ovarian cancer cell line and hence were selected for further fractionation. Six compounds were isolated from these extracts. The structure elucidation and characterization of these compounds was carried out using mass spectrometry and 1D and 2D NMR techniques.
The bioassay-guided fractionation of Roupellina (Strophanthus) boivinii yielded three new and one known cardenolide glycosides. The structure of the known cardenolide glycoside was determined after comparison of NMR data to that found in literature for digitoxigenin 3-O-β-D-glucopyranosyl-(1â 4)-α-L-acofriopyranoside. All four compounds exhibited good antiproliferative activity on the A2780 bioassay.
The fractionation of the extract of Grewia sp. led to the isolation of one new and one known triterpenoid. The known triterpenoid was identified as 7β-hydroxy-23-deoxojessic acid and its structure was confirmed by comparison of its 1D and 2D NMR data to that found in literature.Master of Science
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Wong, Ho-fai, and 黃浩輝. "Applications of high field nuclear magnetic resonance spectroscopy to the structure elucidation, conformational anslysis and asymmetricsynthesis of natural products." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B29747715.
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Ebrahim, Weaam Nabil El Sayed [Verfasser], and Matthias U. [Akademischer Betreuer] Kassack. "New Natural Products from Endophytic Fungi-Structure Elucidation and Biological Activity / Weaam Nabil El Sayed Ebrahim. Gutachter: Matthias U. Kassack." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2012. http://d-nb.info/1023128330/34.
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Ortlieb, Nico Verfasser], and Timo H. J. [Akademischer Betreuer] [Niedermeyer. "Characterization of Natural Products from Actinobacteria of the Tübingen Strain Collection – Screening, Isolation & Structure Elucidation / Nico Ortlieb ; Betreuer: Timo Niedermeyer." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1190639777/34.
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Ortlieb, Nico [Verfasser], and Timo H. J. [Akademischer Betreuer] Niedermeyer. "Characterization of Natural Products from Actinobacteria of the Tübingen Strain Collection – Screening, Isolation & Structure Elucidation / Nico Ortlieb ; Betreuer: Timo Niedermeyer." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1190639777/34.
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Orfali, Raha [Verfasser], Peter [Akademischer Betreuer] Proksch, and Matthias U. [Akademischer Betreuer] Kassack. "Natural Products from Plant and Hypersaline Sediment Derived Fungi-Structure Elucidation and Biological Characterization / Raha Orfali. Gutachter: Peter Proksch ; Matthias U. Kassack." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2015. http://d-nb.info/106635927X/34.
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Dolan, Jamie Marie. "'Do Good Things for the Fish': Organizational Innovation in Tribal Governance." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195674.
Full textAbstract:
This dissertation examines the organizational aspects of fish and wildlife management for Native American nations. Fish and wildlife management is an arena of great importance to many Native nations in subsistence, economic and cultural realms. Additionally, fish and wildlife, being common-pool resources, offer interesting management challenges. My research focuses on what happens when Native American nations exercise self-determination in this arena which requires them for both political and practical reasons to interact with state and federal governments and for economic reasons to deal with markets, all while attempting to meet the needs of their nations. Using fuzzy-set qualitative comparative analysis and drawing upon survey and case study research with Native American fish and wildlife programs, I examine how tribes manage their fish and wildlife resources and with what results.This research helps identify under what conditions tribes may achieve various management goals. In some important ways, tribes are limited in what they can do, particularly in regards to land base size and degree of jurisdiction over non-Indians. More importantly, however, this research identifies some of the many ways tribes can work to take charge of or support tribal fish and wildlife management without having to appeal to outsiders. While there are some very real limitations to fish and wildlife management external to tribes, within those limits, tribes have opportunities to assume and be effective in resource management.This dissertation also provides evidence to suggest that as tribes are better able to determine their own management and governance paths, elements of clan structures and logics develop where the organizational literature would predict they would not. Studying tribal fish and wildlife programs in particular offers an examination of these clan-like features typically found only on the societal fringes. Perhaps even more importantly, this dissertation research demonstrates that there are different governance structures, or logics, co-existing and operating in hybrid forms. For tribes, these hybrid structures create some challenges and inconsistencies that more pure governance structures would not. Nevertheless, these hybrid structures also allow for flexibility and effectiveness in responding to the diverse stakeholders invested in or influencing tribal fish and wildlife management.
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Johnson, Garrett. "Structure Elucidation of a Pyrrolobenzodiazepine Alkaloid and a Biologically Active Polyketide Produced by Rhodococcus sp. MTM3W5.2 via Two-Dimensional NMR Spectroscopy." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etd/3681.
Full textAbstract:
As the battle against ever-increasing drug resistence bacteria rages on, novel and sometimes more complex natural products can be used to combat this. In this study, two-dimensional NMR techniques were utilized to collect a complete spectral data set for two natural products. The first structure, a synthesized Pyrrolobenzodiazepine alkaloid natural product was confirmed through these methods. The second, a strain of Rhodococcus, MTM3W5.2, produces a novel antibacterial molecule in broth cultures and the active compound was fractionated using a Sephedex LH-20 column. Chromatographic purification yielded a pure sample at 58.90 minutes, RT.58. HRMS data deduced an exact mass of 911.5490 Da, equivalent to a molecular formula of C52H78O13. Several major spin systems were constructed from the 2D-NMR spectra. However, due to limited sample quantity in compound with a large molecular weight and product instability, the long range HMBC signals needed to connect these fragments have not yet been obtained.
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Bringmann, Gerhard, Joan Mutanyatta-Comar, Katja Maksimenka, John M. Wanjohi, Matthias Heydenreich, Reto Brun, Werner E. G. Müller, Martin Peter, Jacob O. Midiwo, and Abi Yenesew. "Joziknipholones A and B : the First Dimeric Phenylanthraquinones, from the Roots of Bulbine frutescens." Universität Potsdam, 2008. http://opus.kobv.de/ubp/texte_eingeschraenkt_verlag/2010/4263/.
Full textAbstract:
From the roots of the African plant Bulbine frutescens (Asphodelaceae),
two unprecedented novel dimeric phenylanthraquinones, named joziknipholones A and B, possessing axial and centrochirality, were isolated, together with six known compounds. Structural elucidation of the new metabolites was achieved by spectroscopic and chiroptical methods, by reductive cleavage of the central bond between the monomeric phenylanthraquinone and -anthrone portions with sodium dithionite, and by quantum chemical CD calculations. Based on the recently revised absolute axial configuration of the parent phenylanthraquinones, knipholone and knipholone anthrone, the new dimers were attributed to possess the P-configuration (i.e., with the acetyl portions below the anthraquinone plane) at both axes in the case of joziknipholone A, whereas in joziknipholone B, the knipholone part was found to be M-configured. Joziknipholones A and B are active against the chloroquine resistant strain K1 of the malaria pathogen, Plasmodium falciparum, and show moderate activity against murine leukemic lymphoma L5178y cells.
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Breydo, Leonid P. "New mechanisms of DNA damage and non-covalent DNA binding by the antitumor antibiotic Leinamycin." free to MU campus, to others for purchase free online, 2002. http://wwwlib.umi.com/cr/mo/preview?3052153.
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Downey, Theresa E. "INVESTIGATING STRUCTURE AND PROTEIN-PROTEIN INTERACTIONS OF KEY POST-TYPE II PKS TAILORING ENZYMES." UKnowledge, 2014. http://uknowledge.uky.edu/pharmacy_etds/35.
Full textAbstract:
Type II polyketide synthase (PKS) produced natural products have proven to be an excellent source of pharmacologically relevant molecules due to their rich biological activities and chemical scaffolds. Type II-PKS manufactured polyketides share similar polycyclic aromatic backbones leaving their diversity to stem from various chemical additions and alterations facilitated by post-PKS tailoring enzymes. Evidence suggests that post-PKS tailoring enzymes form complexes in order to facilitate the highly orchestrated process of biosynthesis. Thus, protein-protein interactions between these enzymes must play crucial roles in their structures and functions. Despite the importance of these interactions little has been done to study them. In the mithramycin (MTM) biosynthetic pathway the Baeyer−Villiger monooxygenase (BVMO) MtmOIV and the ketoreductase MtmW form one such enzyme pair that catalyze the final two steps en route to the final product. MtmOIV oxidatively cleaves the fourth ring of the mithramycin intermediate premithramycin B (PreB) via a Baeyer−Villiger reaction, generating MTM’s characteristic tricyclic aglycone core and highly functionalized pentyl side chain at position 3. This Baeyer−Villiger reaction precedes spontaneous lactone ring opening, decarboxylation, and the final step of MTM biosynthesis, a reduction of the 4′- keto group catalyzed by the ketoreductase MtmW.
Another example of co-dependent post-PKS tailoring enzymes from the gilvocarcin biosynthetic pathway is composed of GilM and GilR. These two enzymes form an unusual synergistic tailoring enzyme pair that does not function sequentially. GilM exhibits dual functionality by catalyzing the reduction of a quinone intermediate to a hydroquinone and stabilizes O-methylation and hemiacetal formation. GilM mediates its reductive catalysis through the aid of GilR that provides its covalently bound FADH(2) for the GilM reaction, through which FAD is regenerated for the next catalytic cycle. A few steps later, following glycosylation related events unique to each gilvocarcin derivative, GilR dehydrogenates the hemiacetal moiety created by GilM to establish the formation of a lactone and the final gilvocarcin chromophore. To achieve a better understanding of post-type II PKS tailoring enzymes and their protein-proteininteractions for the benefit of future combinatorial biosynthetic efforts two specific aims were devised.
Specific aim 1 was to investigate the structure of MtmOIV and the role of active site residues in its catalytic mechanism.
Specific aim 2 was to integrate the function of GilM and its protein-protein interactionswith GilR that lead to their synergistic activity and sharing of GilR’s bicovalently bound FAD moiety.
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Davies, Gwilym. "Natural and bioinspired silk spinning." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:e7ec14e5-efff-4e19-b1a0-4c9f02ade678.
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This thesis describes an investigation into silk spinning, with the objective of producing high performance silk fibres in the laboratory using a novel spinning device based upon observations on natural spinning glands and processes. After an in-depth literature review the work is reported in two sections: natural and artificial spinning. The literature provides fragmented data on different aspects of natural silk production, and artificial spinning has not yet reproduced fibres with the properties of native silk fibres, despite unfounded claims of biomimetic spinning. The first half of the thesis looks at natural silk spinning. The work started with a general study of the morphology of spider and silkworm spinning ducts: First, how the silk fibre develops as the dope flows through the gland; and second the relationship between silk fibre properties and both gland morphology and spinning speed. More detailed studies using histochemical and spectroscopic investigations showed that the silk ducts of the spider Nephila edulis and the silkworm Bombyx mori both contain β-chitin, despite an evolutionarily distant common ancestor. Finally, observations showed that the duct of N. edulis consists of alternating nanoporous discs, and FEA modelling indicated that the duct is optimised for mechanical integrity and permeability. The second half of the thesis describes the development of a spinning device that uses natural silk dope mainly taken from B. mori as feedstock. It begins with a description of the gradual development of the engineering aspects of the spinning device, to meet challenges raised during the spinning investigation. The development of a centrifugal capillary rheometer, for practical quantitative insights into rheological processes is then presented. Finally the spinning investigation is reported: first, the screening of spinning in glass capillaries based upon natural gland dimensions and flow rates, which have been shown to induce fibrillation in silk dope in a rheometer, and also included initiation of instability through heat applied along the capillary; second, the final spinning evaluation, using lessons learned from all the screening trials throughout the project, but also including a key development of a hydrophobic coating on the capillary tip to inhibit droplet formation and massively increase the process stability and ease of fibre production. The main conclusions from this work are that good silk fibre cannot be spun by flow shear stress alone; and, that heat instability induces indiscriminate gelation of the silk, whose disordered molecular structure gives poor silk fibre properties. The body of work behind these conclusions provides fundamental background information and new insights that will contribute to the next stages of development of artificial silk spinning, from obtaining a better understanding of the biology of natural spinning glands to the engineering difficulties of implementing the bioinspired principles.
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Just, Baringo Xavier. "Thiopeptides: Synthesis and Structure-Activity Relationship Studies." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/128268.
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The present doctoral thesis has been devoted to the development of a new synthetic strategy to obtain a new member of the thiopeptide, or thiazolyl peptide, family of antibiotics. This new member, baringolin, was isolated and characterized by the Spanish pharmaceutical company Instituto Biomar S.A. Although a structure was proposed, no stereochemical information was provided. Thus, this thesis has several objectives; first, a novel modular and straightforward strategy must be developed to achieve its total synthesis, but also to facilitate the preparation of analogues. The achievement of the total synthesis of baringolin should serve as the final confirmation of its structure and stereochemistry.
The strategy developed herein is based in cross-coupling reactions and required the preparation of suitable building blocks and optimization of the required methodology. Moreover, L –series amino acids were chosen as the sole source of chirality to be introduced in the molecule, which is presumably synthesized in the ribosome of the producing bacteria.
Once the synthetic methodology was set up and building blocks were ready, condensation of all fragments and final steps gave rise to synthetic baringolin, which was identical to its natural counterpart, confrming its structure and stereochemistry. Comparison of both products was made by spectroscopic methods and biological function assessment.
Given the successful outcome of our synthetic plan, a small library of analogues was designed. Two different moieties of the molecule were modified: the thiazoline ring and the peptidic tail. As a result of minimum inhibitory concentration of Gram positive bacteria growth assessment of the library, different conclusions could be drawn from the results thus obtained. First, thiazoline was shown to be crucial to keep a broad activity profile against many strains; its substitution for a more rigid thiazole ring resulted in loss of activity towards most strains, while potency was only maintained against S. aureus. On the other hand, shortening of the peptidic tail had almost no effect in either activity or potency. Substitution of the peptidic tail with a cyclohexanoic acid moiety in the thiazole series resulted in recovery of activity against all strains and a potency increase against most of them.
The good results obtained are good evidence of the efficiency of the synthetic strategy developed during this thesis and demonstrate that chemical synthesis is a useful tool for both structure determination and structure-activity relationship studies.En la presente tesis doctoral se ha llevado a cabo el desarrollo de una nueva estrategia sintética para la obtención de un nuevo miembro de la familia de antibióticos conocida como tiopéptidos, o tiazolil péptidos. Este nuevo miembro, la baringolina, fue aislado y caracterizado por la empresa farmacéutica española Biomar S.A., la cual no elucidó la estereoquímica del compuesto. Así, el propósito inicial de esta tesis es múltiple; por un lado se pretende desarrollar una estrategia que permita su obtención de forma directa y modular, facilitando la futura síntesis de análogos; por otro lado, la obtención de la baringolina sintética debe ofrecer una confirmación definitiva de su estructura y su estereoquímica. La estrategia desarrollada se basó en reacciones de acoplamiento cruzado, lo cual requería la preparación de los fragmentos necesarios y la optimización de la metodología a utilizar. Además, se escogió utilizar amino ácidos de la serie L como única fuente de quiralidad en la molécula, la cual presumiblemente está formada a partir de estos, dado el origen ribosomal de los tiopéptidos. Con la metodología puesta a punto y los fragmentos correspondientes preparados, se pudo llevar a cabo su ensamblaje, dando lugar a la baringolina sintética, la cual resultó ser idéntica a la natural, confirmándose así su estructura y estereoquímica. Dado el éxito de la síntesis total, se procedió a la síntesis de una pequeña librería de análogos, en la cual se modificaron dos zonas diferentes de la molécula, el anillo de tiazolina y la cola peptídica. Como resultado de la evaluación de la capacidad de inhibición de cultivos de bacterios Gram positivo, se extrajeron diversas conclusiones relativas a las relaciones estructura-actividad de las partes modificadas. En primer lugar, la tiazolina demostró ser necesaria para mantener un amplio espectro de actividad frente a diversas cepas, ya que su substitución por un anillo de tiazol, más rígido, prácticamente solo mantuvo el mismo nivel de potencia frente a S.aureus. Por otro lado, el papel de la cola peptídica resultó ser limitado, ya que su acortamiento no causó grandes diferencias de actividad y potencia. Por último, se substituyó la cola por un grupo de ácido ciclohexanoico en la versión que poseía un anillo de tiazol en lugar de tiazolina, lo cual resultó en el restablecimiento de la actividad frente a todas las cepas y un aumento de potencia frente a la mayoría de estas.
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Mwanza, Patrick. "Determination of the effects of sunlight and UV irradiation on the structure, viability and reapplication frequency of the biopesticide cryptophlebia leucotreta granulovirus in the protection against false codling moth infestation of citrus crops." Thesis, Nelson Mandela Metropolitan University, 2015. http://hdl.handle.net/10948/6346.
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Cryptophlebia leucotreta granulovirus (CrleGV-SA) is a baculovirus specifically pathogenic to the citrus pest false codling moth, Thaumatotibia leucotreta. CrleGV- SA is formulated as a commercial biopesticide, Cryptogran® (River Bioscience, South Africa). The virus has a stable, proteinaceous crystalline occlusion body (OB) that protects the nucleocapsid. The major limitation to the use of baculoviruses is their susceptibility to the ultraviolet (UV) component of sunlight, which rapidly and greatly reduces their efficacy as biopesticides. The UVA and UVB components are the most destructive to biological organisms. To date no publication has reported the effect of UV on the structure and virulence of CrleGV, or the effectiveness of the OB as a UV protectant. In this study the effect of UV irradiation on the structure and infectivity of pure CrleGV-SA and Cryptogran® was investigated using scanning electron microscopy (SEM), Raman spectroscopy, qPCR, and bioassays. The project included laboratory and field studies. In the laboratory, CrleGV-SA and Cryptogran® were exposed to either UVA or UVB for periods of 24 hours to 7 days before analysis. In the field, Cryptogran® was applied to trees in a citrus orchard with young fruit. The fruit were collected from 24 hours to 28 days after application and bioassays conducted to assess the effect of sunlight over time on virus structure and efficacy when applied to the northern or southern sides of the trees. No surface morphological changes to the virus were detected using SEM. However, small compositional changes were detected by Raman spectroscopy. qPCR and bioassays demonstrated that UV irradiation damaged the viral DNA, greatly reducing the infectivity of pure CrleGV-SA and Cryptogran®. Exposure to UVB reduced the virulence of the virus more than UVA. The field studies revealed that the activity of CrleGV-SA decreased more on the northern side of the trees than on the southern side.