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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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.
Full textAbstract:
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.
Full textAbstract:
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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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.
Full textAbstract:
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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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.
Full textAbstract:
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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Just, Baringo Xavier. "Thiopeptides: Synthesis and Structure-Activity Relationship Studies." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/128268.
Full textAbstract:
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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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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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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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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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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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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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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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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Álvarez, Bercedo Paula. "Síntesis estereoselectivas de lactonas y compuestos espiroacetálicos de origen natural." Doctoral thesis, Universitat Jaume I, 2008. http://hdl.handle.net/10803/384548.
Full textAbstract:
La Tesis titulada Síntesis estereoselectivas de compuestos lactónicos y espiroacetálicos de origen natural y desarrollada por Paula Álvarez Bercedo ha consistido en la síntesis total de los siguientes productos naturales:
1. Síntesis estereoselectiva de la estructura asignada al producto natural feigrisólido A, lo que ha permitido corregir la estructura no sólo del feigrisólido A y del feigrisólido B, demostrando que sus éstas coinciden con las de los ácidos nonáctico y homononáctico, respectivamente.
2. Síntesis enantioselectiva los espiroacetáles aculeatinas A, B, y D.
3. Síntesis enantioselectiva de la lactona insaturada dodoneína, lo que ha permitido demostrar que la estructura asignada a la misma era correcta, como también su configuración absoluta.
4. Síntesis estereoselectiva de la estructura asignada al pandangólido 1. Los datos espectroscópicos del producto sintético y natural, sin embargo, no coincidían lo que hace necesario llevar a cabo una revisión de las configuraciones absoluta y relativa de este metabolito.
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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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Herraiz, Cobo Jesús. "Mayotlide: synthetic approaches and structural elucidation." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/462881.
Full textAbstract:
Mayotlide is a marine peptide isolated by PharmaMar S.A. from Spongia sp.. The sequence of the aminoacids were achieved by MS-MS spectrometry, where two of them were tryptophans. The NMR spectroscopy revealed the presence of N1-C3a bond between the tryptophans, which means that one of them was cyclized. On the first structure proposal, the aminoacids were forming two macrocyclic rings: on the ring B, all the aminoacids of molecule were tied by amide bond, remarking the presence of the cyclized tryptophan as a hexahydropyrroloindole unit (HPI). The ring A was established by three aminoacids of the ring B: one tryptophan, one isoleucine and the HPI, which became closed by the N1-C3a bond between the two tryptophans. The aminoacid analysis demonstrated the L configuration of all of them, just remaining the HPI with unknown stereochemistry.
Due to the configuration of the HPI system, there can be four diasteromers. To the best of our knowledge, there were not empirical evidences about which one could be more favorable. Hence, a computational study of the ring A through the MOE program was performed, evidencing that the rings A with the exo HPI adducts (L and D) were more stable than the endo ones. Among the exo ones, another computational study with the whole molecule revealed that the mayotlide with the exo-L adduct of the HPI was more stable.
Once that there was established a starting point with the HPI, it was necessary to find out a synthetic strategy that could fulfill the necessary requirements. A methodology developed by Baran and coworkers for the synthesis of the Trp-HPI fragment on molecules related to mayotlide was adapted to our proposal. On the first step of this strategy, under reaction conditions, the starting tryptophan cyclizes, providing exclusively the HPI with the exo configuration, at the same time that the N1-C3a bond between the HPI and 2-iodoaniline is formed. The 2-iodoaniline, along with a disubstituted alkyne, condense together yielding the upper tryptophan without loss of the former stereochemistry, reaching the Trp-HPI framework in two steps with high yields.
Taking advantage of this methodology and an appropriate use of the protecting groups in order to perform the corresponding cyclizations of the two macrocyclic rings, the mayotlide with the exo-L HPI was accomplished. Nevertheless, nor the NMR neither the MS-MS fragmentation pattern of the final compound coincided with the natural product ones. Thus, the next alternative would consist on repeating the synthesis but with the exo-D adduct of the HPI instead.
During the last synthesis, the bibliography and the analytical data of the natural product were extensively revised. There were no documented precedents of natural peptides with the Trp- HPI motif, and the initial structure did not justify the most important data extracted from the MS-MS spectrometry. the main fragmentation concerned to the isoleucine, and on the first proposal such aminoacid was not forming part of a conflictive scaffold. Likewise, among the eight proposed linear sequences for the ring B, the isoleucine just appear in one as C-terminus of the b-ions, when it is one of the aminoacids that forms part of both macrocycles.
The most related family of peptides to mayotlide are the kapakahines. Kapakahines, instead of having a Trp-HPI moiety as the central part of the molecule, exhibit a Trp-α carboline, with an
aminoacid establishing the bridge for a very tensioned tetracyclic system. Such structure may justify the isoleucine fragmentation pattern, but on the other hand the sequence of the aminoacids did not fix. It was necessary to invert the central sequence of the aminoacids to reach out a final structure proposal which justifies all the requirements, relabeled as “kapakahine H”.La mayotlida es un producto natural de origen marino aislado por PharmaMar. SA.. En la primera propuesta que se hizo, se elucidó como un péptido con dos anillos macrocíclicos: en el anillo B estaban contenidos todos los aminoácidos de la molécula, destacando la presencia de una unidad de HPI, que procede de la ciclación intramolecular del extremo amino de un triptófano con el C2 del anillo de indol. El anillo A está formado por tres aminoácidos del anillo B: un triptófano, una isoleucina y el HPI, quedando cerrado por la formación de un enlace entre el N1 del triptófano y el C3a del HPI. El análisis de aminoácidos demostró la configuración L de todos ellos, quedando desconocida la estereoquímica del HPI. El HPI posee tres estereocentros: los C3a y C8a, que siempre están en cis por la propia configuración del anillo y se pueden considerar como un conjunto, y el estereocentro del Cα. Por tanto, son cuatro el número total de diasterómeros posibles. El anillo A con las cuatro posibilidades de HPI fue estudiado energéticamente con el programa MOE, llegando a la conclusión que los aductos exo son más estables que los endo, y que el aducto exo-L es más estable que el exo-D. Para abordar la síntesis de la mayotlida exo-L se adaptó una metodología desarrollada por Phil Baran y colaboradores para moléculas con una estructura relacionada a la mayotlida. Tras conseguir la síntesis de la mayotlida con el aducto exo-L del HPI, se comprueba que los espectros de RMN y de MS-MS presentan grandes divergencias. Ante la incapacidad de interpretar las diferencias existentes entre el producto natural y la mayotlida exo-L, se tomó la decisión de abordar la síntesis de la mayotlida con el aducto exo-D del HPI. En el transcurso de la síntesis exo-D se revisó extensivamente la bibliografía y los datos analíticos relacionados con la mayotlida: no existían antecedentes de productos naturales peptídicos con estructura Trp-HPI, y la estructura no encajaba con los datos más transcendentales del MS-MS. La estructura fue revisada, llegando a la conclusión de que podía pertenecer a la familia de las kapakahines, con una estructura central Trp-α carbolina y con la secuencia central de los aminoácidos invertida, rebautizada como kapakahina H.
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Aragão, Valquiria. "Síntese da estrutura macrocíclica dos furanoeliangolidos." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-16072007-140303/.
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Furanoeliangolidos são produtos naturais bioativos com peculiar estrutura macrocíclica. A síntese orgânica destes compostos tem despertado grande interesse por parte de vários pesquisadores. Particularmente, há alguns anos, o nosso grupo de pesquisa vem se dedicando, entre outras atividades, ao estudo de métodos sintéticos para a preparação do esqueleto estrutural dos furanoeliangolidos, mais especificamente do goiazensolido. A estrutura simplificada deste produto natural corresponde a um sistema 7-oxabiciclo[6.2.1]undecano. Este produto natural possui as seguintes atividades biológicas: esquistossomicida, citotóxica e antiinflamatória. Nossa metodologia utiliza, como etapa chave, a reação de Diels-Alder. Após a preparação do sistema policíclico, a clivagem da ligação interna dos anéis poderia fornecer o macrociclo desejado. Neste trabalho, foram estudadas três rotas sintéticas para preparação do núcleo básico dos furanoeliangolidos. Na proposta sintética inicial, a reação de Diels-Alder realizada entre o 2-metil-furano e o 3-bromopropiolato de metila, apresentou um aspecto surpreendente, uma alta regiosselevidade. A reação de anelação para formação do sistema policíclico foi investigada com três compostos diferentes. Todavia, nenhuma destas reações forneceu o produto desejado, mas sim resultaram em misturas complexas de produtos. Estes resultados revelaram a dificuldade em se realizar reações de anelação em compostos deste tipo. Outros substratos poderiam ser usados, mas considerando esses resultados insatisfatórios, nós preferimos iniciar o estudo de uma nova rota sintética. Na segunda rota, tentamos introduzir um grupo contendo três carbonos para formar o anel de seis membros, a partir de modificação na parte ?superior? da molécula (éster metílico). O aldeído intermediário pôde ser obtido com bom rendimento, mas o produto resultante da condensação aldólica deste composto com a acetona, é muito instável. A hidrólise de cetais deste tipo, conforme verificamos em experimentos com um cetal mais simples, requer tratamento com ácido forte. O produto obtido da reação aldólica, portanto não poderia resistir a essas condições, então abandonamos a rota. Na terceira rota sintética, a metodologia consistiu na construção do sistema policíclico através de duas reações de Diels-Alder e utilizando uma reação de ozonólise para clivar a dupla ligação central. A estereoquímica do aduto obtido na segunda reação de Diels-Alder foi confirmada por estudos de RMN. A ozonólise deste composto deu origem ao macrociclo desejado, contendo o núcleo estrutural dos furanoeliangolidos. Como o grupo imida presente neste macrociclo é muito resistente à hidrólise e outras reações, nós também desenvolvemos uma modificação que produz um produto mais tratável. O dieno utilizado nesta segunda reação de Diels-Alder não fornece aduto com anidrido maleico, mas ele reage bem com o acetilenodicarboxilato de dimetila dando o aduto correspondente. As duas duplas ligações deste composto são suficientemente diferentes uma da outra para permitir a ozonólise seletiva da dupla ligação central, mais nucleofílica. Nesta última rota sintética, dois macrociclos foram preparados em sete etapas, envolvendo duas reações de Diels-Alder, com rendimento total de 36,3% e 42,1%, respectivamente.Furanoheliangolides are bioactive natural products containing a peculiar macrocyclic structure. The synthesis of these compounds has been a matter of considerable interest to several researchers. In the last few years, our research group has dedicated some efforts to develop synthetic methods for the preparation of the core structure of the furanoheliangolides, particularly goyazensolide. The core structure of this natural product corresponds to the 7- oxabicyclo[6.2.1]undecane system. This natural product has several biological activities, such as schistosomicidal, cytotoxic and anti-inflammatory. Our methodology uses, as a key step, the Diels-Alder reaction. After the preparation of the polycyclic system, the cleavage of the internal bond of the rings should furnish the desired macrocycle. In this work, three synthetic routes to the preparation of the core structure of the furanoheliangolides were studied. In the first route, the Diels-Alder reaction between 2-methylfuran and methyl 3-bromopropiolate, occurred with unusually high regioselectivity The cyclization reaction for the formation of the polycyclic system was investigated with three different compounds. However, none of these reactions furnished the desired product, but resulted instead in complex mixtures of products. These results showed the difficulty to perform cyclization reactions in compounds of this type. Other substrates could have been used, but considering these discouraging initial results, we preferred to start the studies of a new synthetic route. In the second route we were still attempting to introduce a three-carbon group to form the new six-membered ring; the main modification was that we would now start from the other side of the molecule. The aldehyde could be obtained in good yield, but the aldol reaction product of this aldehyde with the ketone is very unstable. As we have found in experiments with a simple ketal, the hydrolysis of ketals of this type require rather strong acidic treatment. Therefore, the aldol product would not withstand these conditions, so we abandoned these studies. In the third synthetic route, the methodology consisted of building the polycyclic system through two Diels-Alder reactions followed by an ozonolysis reaction to cleave the central double bond. The stereochemistry of the addut obtained in the second Diels-Alder reaction was confirmed by NMR studies. The ozonolysis of this product produced the desired core of the furanoheliangolides. As the imide group of this macrocycle is very resistant to hydrolysis and other reactions, we have also developed a modification that produces a more treatable product. The diene used in this second Diels-Alder reaction does not give Diels-Alder adduct with maleic anhydride, but it reacts well with dimethyl acetylenedicarboxylate to give correspondent addut. The two double bonds of this addut are sufficiently different from each other to permit the selective ozonolysis of the more nucleophilic central bond. In this last synthetic route, two macrocycles were prepared in seven steps, involving two Diels-Alder reactions, with overall yields of 36.3% and 42.1%, respectively.
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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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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/.
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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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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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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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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.
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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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Miquet, Stéphanie. "Synthèse énantiosélective de terpènes naturels : kopéoline, kopéolone et siphonellinol D." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4343.
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Ce travail développe différentes stratégies pour la synthèse énantiosélective de sesquiterpènes naturels à partir de chirons obtenus par biocatalyse. La première partie est consacrée aux premières synthèses énantiosélectives de la kopéoline, et de la kopéolone. La synthèse de la structure décrite de la kopéoline est réalisée, les composés ont été entièrement caractérisés. Les résultats montrent que les structures reportées n'ont pas été correctement assignées, et suggèrent une mauvaise attribution des stéréocentres au cours de l'isolement des produits naturels. Ainsi, deux nouvelles structures sont proposées. Les synthèses totales de ces deux dernières structures ont également été réalisées et ont permis de confirmer la révision structurelle et de caractériser complètement ces produits naturels tout en élucidant leurs configurations absolues inconnues jusqu'alors.La seconde partie aborde la synthèse du siphonellinol D selon une méthodologie convergente d'une partie Est et d'une partie Ouest. Les deux énantiomères d'un chiron ont été obtenus par dédoublement cinétique enzymatique avec des rendements élevés et d'excellentes énantiosélectivités. À partir de l'énantiomère (1S, 6R), la synthèse de la partie Est est rapportée. Malheureusement, une première méthodologie employant l'énantiomère (1R, 6S) n'a pas permis l'obtention de la partie bicyclique Ouest. Une seconde méthodologie utilisant le géraniol comme substrat a permis l'accès à la partie Ouest du siphonellinol D sous forme racémique. Une réaction de couplage entre ces deux parties a été réalisée avec succès permettant d'envisager de manière optimiste la synthèse du siphonellinol D par ce chemin synthétiqueThis work deals with different strategies used in the course of the enantioselective synthesis of natural sesquiterpenes starting from an enantiopure building block obtained by biocatalysis. The first part is dedicated to the first enantioselective syntheses of kopeolin, and kopeolone. The synthesis of kopeolin was achieved and compounds have been fully characterized. The results showed that the reported structures were not assigned correctly, and suggest an initial structural misassignment during the isolation of the natural products. Thus, two new structures for kopeolin and for kopeolone are proposed. The enantioselective total syntheses of these two proposed structures have been achieved and permitted to confirm the structural revision and to fully characterize these natural products while elucidating their hitherto unknown absolute stereochemistries.The second part is dedicated to the synthesis of siphonellinol D with a convergent methodology of the Eastern part and the Western part. Both enantiomers of this building block were obtained by an enzymatic kinetic resolution in high yields and excellent enantioselectivities. Starting from the (1S, 6R) enantiomer, the synthesis of the Eastern part of Siphonellinol D is reported. Unfortunately, a first methodology using the use of the (1R, 6S) enantiomer failed. A second methodology using geraniol as starting material led to the racemic Western part of siphonellinol D. A coupling reaction were successfully performed allowing us to consider the synthesis of siphonellinol D by this synthetic pathway as optimistic
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Siemon, Thomas [Verfasser]. "Synthesis and Functionalization of Highly Biologically Active Terpene Natural Products − Total Synthesis of (+)-Darwinolide and Semisynthesis of (−)-Englerin A and Structure-Activity Relationship Studies of Analogs / Thomas Siemon." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1205314946/34.
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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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Pearce, Clive Michael. "Structural studies on natural products." Thesis, University of Cambridge, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259614.
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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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Gallagher, Oliver Paul. "Structure and synthesis in natural product chemistry /." [St. Lucia, Qld. : s.n.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16653.pdf.
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Skiredj, Adam. "Accès facile à de nombreux squelettes originaux pour la biologie : Auto-assemblage biomimétique de structures polycycliques complexes." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS176/document.
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Au cours de ce travail, nous avons abordé la synthèse biomimétique sous des angles variés. Une déclinaison des approches bio-inspirées a en effet permis de réaliser plusieurs synthèses totales d'alcaloïdes polycycliques complexes. La biogenèse des substances naturelles considérées est placée au centre de la démarche. Au départ, pour définir la stratégie de synthèse puis, en conclusion, lorsque les synthèses réalisées mènent a des hypothèses biosynthétiques plus abouties.Le squelette des drimentines, alcaloïdes hybrides possédant une partie sesquiterpénique, a été obtenu grâce à une séquence de désaromatisation-cyclisation qui mime l'étape-clé de la biogenèse de ces métabolites spécialisés.Une stratégie d'auto-assemblage par dimérisation a été adoptée afin d'étudier les liens synthétiques et biosynthétiques qui unissent les alcaloïdes marins de la famille des aplysinopsines. Au cours de cette étude, les premières synthèses totales du dictazole B et du tubastrindole B ont été réalisées. De plus, l'obtention d'analogues proches des substances décrites et d'un intermédiaire biogénétique supposé a permis de développer une hypothèse de biogenèse se fondant sur la spontanéité et les réactivités chimiques observés au cours de l'étude. L'application de la catalyse à l'ADN à ces travaux a également conduit à des résultats prometteurs.Enfin, une méthode bio-informatique récente appelée "molecular networking" peut être mise à profit afin d'exploiter la diversité de mélanges synthétiques complexes générés par la mise en présence de quelques précurseurs simples. La démarche s'applique à des mélanges connus dans lesquels la nitraramine ou la nitrarine se forment ainsi qu'à des mélanges inédits pouvant conduire, par exemple, au myrifabral A.Ces études montrent encore une fois que la synthèse biomimétique est un outil puissant pour la synthèse totale de substances naturelles polycycliques complexes et ce de bien des manières. On peut retenir que ces stratégies permettent d'accéder à des cibles extrêmement complexes avec simplicité, sobriété et éléganceThis work features various approaches of biomimetic organic syntheses. Biosynthetic considerations have been placed at the center of our analysis in order to define the synthetic plans and later to propose biosynthetic hypotheses.First, the skeleton of drimentines, hybrid alkaloids containing a sesquiterpenic unit, has been obtained by mimicking the main event of their postulated biosynthesis.In a wider study, the marine alkaloid family of the aplysinopsins has been treated with two total syntheses, of dictazole B and tubastrindole B, as well as a full bio-relevant aplysinopsins’ cascade and the application of DNA catalysis principles to the series.Finally, novel dereplication techniques relying on "molecular networking are currently tested on complex synthetic mixtures to merge one step total syntheses and diversity oriented synthesis
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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)