Rozprawy doktorskie na temat „Natural product”
Kliknij ten link, aby zobaczyć inne rodzaje publikacji na ten temat: Natural product.
Utwórz poprawne odniesienie w stylach APA, MLA, Chicago, Harvard i wielu innych
Sprawdź 50 najlepszych rozpraw doktorskich naukowych na temat „Natural product”.
Przycisk „Dodaj do bibliografii” jest dostępny obok każdej pracy w bibliografii. Użyj go – a my automatycznie utworzymy odniesienie bibliograficzne do wybranej pracy w stylu cytowania, którego potrzebujesz: APA, MLA, Harvard, Chicago, Vancouver itp.
Możesz również pobrać pełny tekst publikacji naukowej w formacie „.pdf” i przeczytać adnotację do pracy online, jeśli odpowiednie parametry są dostępne w metadanych.
Przeglądaj rozprawy doktorskie z różnych dziedzin i twórz odpowiednie bibliografie.
1
Bringans, Scott D. "Studies on natural product derivatives : HIV therapies incorporating marine natural products". Thesis, University of Canterbury. Chemistry, 2001. http://hdl.handle.net/10092/6699.
Pełny tekst źródłaStreszczenie:
CV-N is an 11 kDa, anti-HIV protein that binds strongly to the envelope glycoprotein, gp120, expressed on the outer surface of the free virion and also on HIV-infected cells. As such, it represents an important lead for development of anti-HIV therapeutics. Marine toxins such as the halichondrins have potent in vivo cytotoxicities and are lethal to cells. The combination of this potency of the marine toxins with the unique targeting capability of CV-N has been harnessed to produce conjugates that have the potential to selectively target and eliminate HIV-infected cells.
Three forms of the protein were developed; the native protein itself, a derivative recombinantly produced in E. coli with an extra cysteine at the C-terminal (CV-N-Cys) and CV-N with the lysine side chain amines converted into thiols (thiolated-CV-N).
To facilitate release of the toxin within infected cells an enzymatically-cleavable pHdependent biolinker was incorporated separating the toxin from the protein. The chemistry required for incorporation of protein, biolinker, and toxin, was established through synthesis of fluorescently labelled conjugates capable of reaction with CV-N. Biological testing of these derivatives showed no interference with the anti-HIV activity of the CV-N when conjugated in these model compounds. Synthetic strategies were developed to produce two derivatives of norhomohalichondrin B amine, both containing the cleavable biolinker, but with activation from succinimidyl esters and maleimido groups respectively.
Native CV-N was reacted with the succinimidyl ester derived toxin construct to produce a CV-N-biolinker-toxin conjugate. The maleimido derivative toxin construct was reacted with both CV-N-Cys and thiolated-CV -N to produce closely related CV-N-toxin conjugates. Investigations into the binding properties and cell toxicities of these conjugates is currently underway.
2
Li, I. C. K. "Natural product syntheses". Thesis, University of Southampton, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375675.
Pełny tekst źródła
3
Vollmer, Heidi R. "Biologically active natural product synthesis". Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365780.
Pełny tekst źródła
4
Merifield, Eric. "Aspects of natural product synthesis". Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.258148.
Pełny tekst źródła
5
Longbottom, Deborah Anne. "Polyenoyltetramic acid natural product synthesis". Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620206.
Pełny tekst źródła
6
Hunter, Ruth F. "Benzynes in natural product synthesis". Thesis, University of Manchester, 1989. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.655226.
Pełny tekst źródła
7
Puniani, Evaloni Takavaha. "Novel natural product based anti-anxiety therapy and natural insecticides". Thesis, University of Ottawa (Canada), 2004. http://hdl.handle.net/10393/29155.
Pełny tekst źródłaStreszczenie:
The EtOH extracts of the leaves of Margraviaceae, a relatively rare Central American vine for which ethnobotanical reports suggested possible anti-anxiety properties, showed significant anti-anxiety activity in animal models for anxiety. Subsequent bioassay-guided fractionation of these extracts yielded an EtOAc active fraction (f1). Further bioassay-directed chromatography of (f1), led to the isolation of betulinic acid (3) as the bioactive constituent in 0.01% of dry weight. Six known pentacyclic triterpenoids [( 1a), (1b), (2a), (2b), ( 4), (5a)], six known flavonoids [(6), ( 7), (8a), (8b), (9), ( 10)], chondrillasterol (11), linolenic acid (12 ) and a porphyrin type compound (13) were also isolated.
When (3) was administered at 0.5 mg per kg (possibly less) in a variety of rat and mouse model assays, the activity of (3) was comparable to that of Valium, the most famous member of the benzodiazepines family.
Synthetic derivatives of (3) were prepared and evaluated for anti-anxiety activity. Several of the simple esters appear to have ideal properties as new drug Candidates. In particular, betulinic acid methyl ester or methyl betulinate (3a) exhibited anti-anxiety activity superior to (3). The activity profile of (3a) is such that (3a) can be considered a viable drug candidate.
An excellent relay synthesis of (3) from another closely related natural product betulin (14), that is abundantly available in Eastern Ontario, was developed.
Radioactive 3H-labelled betulinic acid methyl ester ( 3a″) was also prepared in order to facilitate identification of relevant anti-anxiety receptors and the mechanism of action of the compound. This is important since (3) showed no significant binding to any of the 40 anti-anxiety receptors currently implicated in anxiety. Therefore, it appears to act as an anti-anxiety agent via a new mode of action.*
In a second project, the active components of a member of the Piperaceae or Pepper family (P. tuberculatum) from Costa Rica, were isolated and their structures characterized as 5,6-dihydropiperlonguminine (25), 5,6-dihydropiperine (26), piperine ( 27) and piperlonguminine (28).
Extracts from this neotropical plant had been previously demonstrated by our biology collaborators, Professor Arnason's group, to be strongly insecticidal towards a variety of pests including mosquitoes, earwigs and white grubs. Moreover, the P. tuberculatum extracts were as effective as the well-documented Asian (P. nigrum) and African ( P. guineense) Piper species.
Piperamides (25)--(28) were synthesized in sufficient amounts to allow extensive evaluation of their insecticidal properties. Experiments with these piperamides showed that the tertiary and quaternary mixtures have greater-than-additive toxicity compared to single compounds or binary mixtures. That is, these piperamides synergize each other. Compound (25) was the most acutely toxic in mosquito larvae bioassays. The field trials to date indicate a high potential for the development of an effective, relatively inexpensive botanically based insecticide.
Radioactive 3H-labelled piperine (27″ ) was also synthesized for toxicokinetic studies.
*Please refer to dissertation for diagrams.
8
Vogt, Thomas. "Plant natural product glycosyl- and methyltransferases". [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=984745009.
Pełny tekst źródła
9
Thite, Aniket Mohan. "Direct approaches toward natural product synthesis". [Ames, Iowa : Iowa State University], 2007.
Znajdź pełny tekst źródła
10
Sperry, Jonathan. "Biomimetic oxidations in natural product synthesis". Thesis, University of Exeter, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425500.
Pełny tekst źródła
11
Hinks, Jeremy David. "Metal carbenes in natural product synthesis". Thesis, University of Southampton, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393940.
Pełny tekst źródła
12
Elsworth, Jon D. "Prins cyclisations in natural product synthesis". Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445810.
Pełny tekst źródła
13
O'Neil, Ian Anthony. "Novel methods in natural product synthesis". Thesis, Imperial College London, 1986. http://hdl.handle.net/10044/1/38124.
Pełny tekst źródła
14
Bolton, R. E. "Azide decomposition in natural product synthesis". Thesis, Imperial College London, 1986. http://hdl.handle.net/10044/1/37947.
Pełny tekst źródła
15
Durbin, Matthew J. "Palladium catalysis for natural product synthesis". Thesis, University of Bath, 2007. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.519010.
Pełny tekst źródłaStreszczenie:
This thesis details investigations towards the total synthesis of the naturally occurring alkaloid hodgkinsine, utilising palladium catalysis to achieve desymmetrisation of a meso-chimonanthine derivative. Initially, a Suzuki cross-coupling approach was envisaged. Meso-chimonanthine is functionalised as its C-7 bisiodide derivative by directed ortho-lithiation. Suitable electrophiles are screened for the successful preparation of additional bisbromide and bistriflate derivatives to broaden the scope of the cross-coupling. The synthesis of a suitable indole-3-boronic ester coupling partner is also achieved. Investigations into the post-Suzuki coupling elaboration of the indole moiety were conducted with model substrates to assess the viability of a proposed alkylation-cyclisation procedure. C-3 alkylation of various N-protected C-3 phenylindole derivatives was unsuccessful when employing aziridines, sulfamidites and sulfamidates as electrophilic two carbon fragments. Therefore a second generation boronic ester with latent enolate functionality for increased nucleophilicity was prepared in six high yielding steps from oxindole, via trapping 3-bromo-N-BOC-oxindole as the TIPS enol ether and subsequent C-3 palladium catalysed borylation. The Suzuki coupling of the new boronic ester with meso-chimonanthine derivatives was shown to be unsuccessful in a broad range of anhydrous and aqueous solvent systems. Palladium catalysts, ligands, bases and measures to reduce steric interactions were all screened in an attempt to achieve coupling. Subsequently the palladium catalysed arylation of N-protected oxindole enolates is developed; aryl bromides, chlorides and triflates are all suitable coupling partners, whilst a broad range of ortho, meta and para functionalised arenes are well tolerated providing C-3 aryl oxindoles in high yield. Extension of this methodology to a C-7 bisbromo meso-chimonanthine substrate was successful, furnishing the desymmetrised product under racemic conditions in 45% yield with the dicoupled product also observed in 20% yield.
16
Zhang, Qian. "Natural Product Drug Discovery Targeting Cancer". Thesis, Griffith University, 2017. http://hdl.handle.net/10072/370435.
Pełny tekst źródłaStreszczenie:
Chemotherapy is one of the most effective approaches for cancer treatment. However, to improve efficacy, the therapeutic targets should be identified and characterised. Moreover, new drugs need to be discovered and developed to target different cancer pathways. Current therapeutics can eliminate most of the cancer cells. However, recurrence and metastasis still remain a major failure of cancer therapy. Emerging evidence demonstrates that multidrug resistance (MDR) and the existence of cancer stem cells (CSCs) are two major contributors for the failure of chemotherapy. MDR is a phenomenon in which cancer cells become resistant to structurally and functionally unrelated anticancer agents. CSCs are a small population of cells within cancer cells with capacity for self-renewal, tumor metastasis and differentiation. CSCs are also believed to be associated with chemoresistance. Thus, MDR and CSCs are the greatest challenges for cancer chemotherapy. Significant effort has been made to search for agents that specifically target MDR cells and CSCs. Consequently, some agents derived from nature have been developed to overcome MDR and CSCs. However, the developed chemotherapeutics cannot be used for all the cancers and some of them display severe cytotoxicity. Hence, there is an urgency to investigate the mechanism of drug resistance and to characterise cancer stem cells to identify potential new therapeutic targets. Natural products lie in the heart of the drug discovery. The developed chemotherapeutic compounds mainly originates from the secondary metabolites of microbes, terrestrial plants and marine organisms. In this study, MDR cancer cells were derived from tissue cultured cancer cells by the treatment the cells with fluorouracil (5-FU) and cisplatin (CDDP). CSCs were developed by treatment in serum-free medium with different factors. Fractions and compounds from Nature Bank (Griffith Institute for Drug Discovery, Griffith University), Compounds Australia (Griffith Institute for Drug Discovery, Griffith University) and Traditional Chinese Medicine (TCM) were screening by high through-put screening (HTS). As a result, one potential anticancer flavonoid was isolated from the Australian plant Cryptocarya (QID025519) which was identified by NMR spectroscopic data, in combination with LC-MS. Extracts, fractions and isolated pure compounds from Bruguiera gymnorrhiza andSchisandraviridis were identified as potential agents for the treatment of tongue cancer and breast cancer. The DCM and MeOH extracts and HPLC fractions of B. gymnorrhiza showed antiproliferation activity against cancer cells in a concentration-dependent manner. Further purification of the active fractions led to the isolation of five flavonoids namely rutin, myricetin 3-rutinoside, methoxyflavone, 5-Methoxyluteolin, and 7,3',4',5'-tetrahydroxy-5- gramrione. All five compounds showed antiproliferation activity against CAL27 and MCF7 and MDR cells in a concentration-dependent manner. Methoxyflavone demonstrated the strongest anticancer potential against CAL27 cells, MCF7 cells, CAL27 MDR cells while 7,3',4',5'-tetrahydroxy-5- gramrione illustrated the highest inhibitory effect on MCF7 MDR cells. Both aqueous and ethanol extracts showed activities against MCF7 and CAL27 cancer cells. Bioassay-guided fractionation and purification of the extracts from S.viridis resulted in six active principles, including five dibenzocyclooctene lignans namely gomisin H (1), schisandrin (2), angeloylgomisin H (3), (+)-gomisin M2 (4) and rubschisandrin (5), and one terpenoid, schisanol (6). Compounds 1-3 showed moderate anticancer activities with an IC50 value ranging from 100-200 μg/mL against MCF7 and CAL27 cell lines. Dioxane containing lignans 4-5 and triterpenoid 6 were 10 times more active with IC50 values of14.5, 13.4, 10.6 μg/mL against MCF7, and 21.2, 17.9, 11.7 μg/mL against CAL27, respectively. In addition, two compounds from Compounds Australia exhibited a potential application prospects for tongue cancer and breast cancer therapy. One compound SN00802961 exhibited significant inhibition on MCF7 cells, but low inhibitory effects on fibroblast cells. Meanwhile, it exhibited moderate inhibition on CAL27 MDR cells, CAL27 cells and CSCs. Compound SN00802961 has potently targeted the MAPK/ERK1/2 signaling pathway to induce cytotoxicity in MCF7 cells. Another agent SN00771077 for breast cancer cells in vitro was investigated. The effects of compound SN00771077 on cell viability in vitro were evaluated by treatment of MCF-7 and T47D cells. An in vitro viability assay demonstrated that compound SN00771077 inhibited the cell growth in a dose-dependent manner. The antiproliferative activity of compound SN00771077 is related to its activity on monomeric actin and the subsequent inhibition of polymerization of G-actin monomers. Exposure to compound SN00771077 induced the inhibition of Raf/MEK/ERK pathway in T47D cells. All the results indicated that compound SN00771077 had a strong cytotoxic effects on cancer cells, and shows potential in the treatment of breast cancer by causing the depolymerizing actin cytoskeleton.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
Full Text
17
McArdle, Bernadette. "Natural Product Interactions with Biology Space". Thesis, Griffith University, 2007. http://hdl.handle.net/10072/366724.
Pełny tekst źródłaStreszczenie:
Natural products have withstood the test ot time as therapeutics but new lead generation strategies have focused away from natural products. This study reports a new approach that uses natural product recognition to drive an understanding of biology space which may provide an impetus for renewed focus on natural product starting points.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Eskitis Institute for Cell and Molecular Therapies
Science, Environment, Engineering and Technology
Full Text
18
Liu, Yunqi. "Synthetic approaches toward natural product synthesis". Diss., The University of Arizona, 1995. http://hdl.handle.net/10150/187050.
Pełny tekst źródłaStreszczenie:
1,2-Dithiolan-3-one-1-oxide exists in antihumor antibiotic leinamycin and can cause DNA cleavage in the presence of thiols. Diastereoselective synthesis of this unique ring system has been achieved by low temperature oxidation of the corresponding 1,2-dithiolan-3-ones with 3,3-dimethyldioxirane. 5-Methyl-1,2-dithiolan-3-one-1-oxides were synthesized by oxidation of 5-methyl-1,2-dithiolan-3-one with 3,3-dimethyldioxirane. Eu(fod)₃ and C₆D₆ induced proton chemical shift studies showed that the major isomer in the product has a trans sulfoxide relative to the 5-methyl group. Low temperature oxidation of 4-substituted-amino-5,5-dimethyl-1,2-dithiolan-3-ones by 3,3-dimethyldioxirane preferentially led to the corresponding trans-1,2-dithiolan-3-one-1-oxides. This assignment was made on the basis of a X-ray crystallographic structure study. Formation of azlactones as well as 1,2-dithiolan-3-one-1,1-dioxide were also observed when some substituted 1,2-dithiolan-3-ones were oxidized by 3,3-ditnethyldioxirane. Three 2,2-dimethyl-1,3-dithian-4-ones were synthesized by SnCl₄ mediated condensation of β-mercaptothioacids and acetone. Oxidation of 2,2,6-trimethyl-1,3-dithian-4-one with Ce(IV) did not give 1,2-dithiolan-3-one or 1,2-dithiolan-3-one-1-oxides as anticipated; 1,3-dithian-5-en-4-one was detected as the product instead. Synthetic approaches toward loline were explored. Intramolecular photoaddition of bicyclic olefinic N-nitrosamine did not give the desired product. An epoxide approach did not furnish loline due to unsuccessful epoxide ring opening by azide ion. In the urea approach, the tertiary nitrogen of the bicyclic urea preferentially undergoes a transannular iodocyclization. The same results were obtained by halocyclizing bis-silylimidate or mono-silylimidate of the bicyclic urea.
19
Jensen, Mari N. "UA Licenses Patent for Natural Fungicide: Natural Product Fights Plant Diseases". College of Agriculture and Life Sciences, University of Arizona (Tucson, AZ), 2005. http://hdl.handle.net/10150/622198.
Pełny tekst źródła
20
Wallace, Stephen. "A cascade approach towards the gephyrotoxins". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:1f7b55ec-0346-498c-be03-81f3b9fde2f5.
Pełny tekst źródłaStreszczenie:
The aim of this project was to develop a cascade approach towards perhydropyrrolo-[1,2-a]-quinolines and to apply this to the asymmetric synthesis of the gephyrotoxin alkoids. Chapters Two and Three outline the development of a synthetic route towards a range of cascade precursors, whilst Chapter Four outlines investigations into the enamine-Michael cascade. Central to understanding the cascade process was the discovery that the major product of the enamine-Michael cascade was the unusual tricyclic hydroquinium salt. This can subsequently be engaged in a diastereoselective inter- or intramolecular reduction to afford either a trans-perhydro-[1,2-a]-quinoline or a tetracyclic aminal in high overall yield depending on the C1 oxygen substituent.
21
Ghirardi, Elena. "Enantio- and Diastereoselective Cyclocondensation Reactions. Stereocontrolled Access to Azabicycles and Application to Natural Product Synthesis". Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/398789.
Pełny tekst źródłaStreszczenie:
The first objective of this Thesis was the study of the preparation of octhydro-1H-cyclopenta[b]pyridines and octahydro-1H-indoles, through the synthesis of (R)-phenylglycinol derived tricyclic lactams. Following the previous reported methodology a carbon substituent would be present at the carbocyclic ring and we planned to find the conditions for controlling its absolute configuration. Unfortunately, the reaction of ketoester 4 and ketoacid 7, provided undesired enamines 8 and 9. On the other hand, the reaction of ketoacid derivatives 16 and 17 with (R)-phenylglycinol led to a mixture of epimeric amides 18.
With the aim to extend the methodology, we planned to study the cyclocondensation reaction of (R)-phenylglycinol and (1S, 2R)-aminoindanol with C-3 and C-5 substituted cyclohexanepropionate derivatives. These reactions provided enantiopure tricyclic or pentacyclic lactams: in every run, a major lactam was isolated or identified, and a minor one was detected. The use of (1S, 2R)-aminoindanol resulted in better results. These tricyclic and pentacyclic lactams are precursors of C-8 (and C-6,8) substituted cis-decahydroquinolines. The conversion required the stereoselective reductive cleavage of C-O oxazolidine bond with simultaneous reduction of lactam carbonyl group, and debenzylation. A library of enantiopure cis-decahydroquinolines was obtained. To illustrate the usefulness of our method, we decided to undertake the synthesis of some alkaloids of Myrioneuron nutans family, which contain an 8-substituted cis-decahydroquinoline core. In particular, we prepared the enantiopure alcohol 82, which was described to be a common intermediate in the synthesis of various Mirioneuron nutans alkaloids. Our synthetic procedure greatly improved the previous results reported for the synthesis of this alcohol.
The cyclocondensation reaction of (R)-phenylglycinol and (1S,2R)-aminoindanol with 3-alkyl-2-oxo-cyclohexane-1-acetate derivatives was finally considered. Reaction of (R)-phenylglycinol and 3-alkyl-2-oxocyclohexaneacetate derivatives 97-100 and 107 provided with high yield and stereoselectivity tricyclic lactams 110, 112a, 114, 116 and 118, which incorporate an alkyl or aryl substituent at C-10, while (1S,2R)-aminoindanol did not furnish so good outcomes. These reactions stereoselectively provided an additional minor hexahydroindole by-product. The absolute configuration of these compounds 111a, 113a, 115a and 117a was confirmed by X-ray crystallography. In the case of any or aryl substituent at C-10 of the tricyclic lactam, no by products were detected. We demonstrated that these unsaturated products derived from the opening of the oxazolidine ring of the minor lactams, which are epimers at C-10 of the major lactams, in the presence of acids. The stereoselective opening of the oxazolidine ring of the major lactams, in the presence of strong acids provided unsaturated compounds 111b, 113b, 115b and 117b, in which H-7 and H-7a resulted in cis relative disposition. In the case of lactam 118, with an aryl substituent at C-10, provided the unsaturated compound 125, in which H-7 and H-7a are in relative trans disposition. This different relative configuration can be accounted for by considering the structure rigidity of this system.
Major tricyclic lactams were converted into C-7 exo substituted cis-octahydroindoles and cis-octahydroindolones, by selection of the appropriate reductive conditions. Hexahydroindolones 111b, 113b, 115b and 117b were converted stereoselectively into the corresponding enantiopure C-7 endo substituted cis-octahydroindolones, by catalytic hydrogenation of the carbon-carbon double bond, followed by elimination of the chiral inductor through reaction with sodium radical. Moreover, these hexahydroindolones and 125 were transformed into the corresponding trans-octahydroindolones 146c-149c and 126b by simultaneous reduction and debenzylation in sodium ammonia. The presence of the amide function allowed the stereoselective insertion of a new substituent by a-alkylation and a-amidoalkylation.
Finally, in order to demonstrate the utility of this methodology, (+)-a-Lycorane was synthesized in only four steps, starting from easily available ketone 171, in 35% of overall yield, which resulted an improvement with respect to previously reported synthesis.El primer objetivo de esta Tesis Doctoral ha sido el estudio de la preparación de octahidro-1H-ciclopentapiridinas y octahidro-1H-indoles, a través de la síntesis de lactamas tricíclicas derivadas del (R)-fenilglicinol. Desafortunadamente, la reacción del ceto-éster 4 y del ceto-ácido 7, proporcionó solamente las eniminas 8 y 9. Por otro lado, la reacción de los derivados de ceto-ácidos 16 y 17 con (R)-fenilglicinol rindió únicamente una mezcla de productos 18, amidas conjugadas epímeras en la posición C-7a. Se ha sido estudiado la reacción de ciclocondensación de derivados de 2-oxociclohexano propionato convenientemente sustituidos en C-3 o en C-3 y C-5 con (R)-fenilglicinol y (1S,2R)-aminoindanol. Esta reacción conduce estereoselectivamente a lactamas tricíclicas o pentacíclicas quirales: se aisló mayoritariamente una lactama y se detectó la presencia de otra minoritaria. Al utilizar (1S,2R)-aminoindanol se obtuvieron mejores resultados. Estas lactamas son precursoras de cis-decahidroquinolinas, con sustituyentes en la posición 8 o en la posición 6 y 8. Las etapas clave de esta transformación son la reducción con alano y la eliminación del inductor quiral. Con esta metodología se ha preparado la decahidroquinolina 82, precursor de numerosos alcaloides de la familia Mirioneuron nutans. Además, presentamos el estudio de las reacciones de ciclocondensación con (R)-fenilglicinol a partir de ciclohexanonas que poseen una cadena de acetato en la posición C-1 y diversos sustituyentes alquilo o arilo en la posición C-3. Esta reacción conduce estereoselectivamente a una sola lactama tricíclica de las ocho posibles. A partir de las cetonas con un sustituyente alquilo en la posición C-3 aislamos una cantidad variable de enamida. Las lactamas mayoritarias, fueron convertidas en cis-octahidroindoles y cis-octahidroindolonas, que presentan un sustituyente en la posición 7 o en las posiciones 7 y 7a del anillo carbocíclico. Además, estudiamos la reactividad de las lactamas tricíclicas en medio ácido: la reacción con TiCl4 en THF, proporciona lactamas insaturadas con elevada estereoselectividad y buen rendimiento. La presencia de la función enamida, nos permitió preparar selectivamente nuevas cis y trans octahidroindolonas. Esta metodología nos permitió sintetizar el (a)-Licorano, un metabolito de la familia de las Amaryllidaceae.
22
Catterick, David. "The parallel synthesis of natural product families". Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299756.
Pełny tekst źródła
23
Rodil, Sandra Beltran. "Novel tandem processes and natural product studies". Thesis, University of York, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533505.
Pełny tekst źródła
24
Ma, Wai Sheung. "Natural Product Drug Discovery against Tropical Diseases". Scholar Commons, 2011. http://scholarcommons.usf.edu/etd/3224.
Pełny tekst źródłaStreszczenie:
This dissertation describes the isolation of secondary metabolites from natural origins through a series of chromatographic techniques and spectrometric characterization in the effort of drug discovery. The isolated compounds obtained were used as drug leads against tropical diseases, namely malaria and leishmaniasis. While first chapter offers an introduction on the use of a natural product by itself as an effective therapeutic and its role on inspiring the discovery of new drugs, the later chapters will concentrate on isolation and characterization of bioactive natural products from an Antarctic sponge and mangrove endophytic fungi during the dissertation work.
The second chapter describes the attempt to develop a new method of solving the absolute configuration of tertiary alcohol using lanthanide chiral shift reagent and 13C NMR spectroscopy. The third chapter describes the isolation of five new steroids, norselic acids A-E, from Crella sp. collected in Antarctica. The structures of the norselic acids were established by NMR and MS techniques. The absolute stereochemistry of norselic acid A was elucidated by SXRD. The antimicrobial and anti-leishmania activities of norselic acid A have been studied. Norselic acid A displays antimicrobial activities against methicillin-resistant S. aureus (MRSA), S. aureus, E. faecium, and C. albicans. Norselic acids B-E exhibit mild antimicrobial activities. All norselic acids exhibit strong cytotoxicity against leishmania.
The fourth and fifth chapters describe a Medicine for Malaria Venture (MMV) funded malaria bioassay-guided screening program. The chemical investigation of the crude endophytic fungal extracts has led to the isolations of a series of known cytochalasins along with the discovery of a few new compounds, including a new simple carboxylic acid, and several known and novel compounds belonging to the dimeric xanthone family. Majority of the cytochalasins display mild cytotoxicity and outstanding inhibition to chloroquine-resistant reference strain Plasmodium falciparum (W2) with IC50 ranging from 25.8 nM to 2900nM. However, their cytostatic properties hinder them from being a good drug candidate. The dicerandrols display good activity with the lowest IC50=0.63 μM against malaria with low cytotoxicity. The structures of the compounds isolated and the associated anti-malarial activities are reported herein.
25
Walker, Deborah Anne. "Synthetic approaches towards the natural product forskolin". Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283449.
Pełny tekst źródła
26
Leadbeater, Claire. "Natural product biosynthesis : mechanistic and enzymatic studies". Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/15194.
Pełny tekst źródłaStreszczenie:
The gene encoding the E. coli flavodoxin NADP+ oxidoreductase (FLDR) has been overexpressed in E. coli and purified to homogeneity. The molecular mass of FLDR apoprotein was determined as 27648 Da. The midpoint reduction potentials of the oxidised/semiquinone and semiquinone/hydroquinone couples of FLDR (-308mV and -268mV, respectively) were measured using redox potentiometry. FLDR was fully characterised kinetically both by steady state and pre-steady state techniques. Arginines (R144, R174 and R184) in the proposed NADPH binding site of E. coli flavodoxin NADP+ oxidoreductase (FLDR) were replaced by alanines and the mutant enzymes fully characterised and studied by pre-steady-state and the steady-state kinetics. From our studies R174 and R184 appear to interact with the adenosine ribose 2' phosphate, while R144 is more likely to stabilise NADPH binding by interaction with the nicotinamide ribose 5' phosphate. R174A and R184A are more efficient enzymes than wild-type or R144A with NADPH as substrate, consistent with the proposed phosphate-binding roles for these residues. Arginine residues R237 and R238 in the proposed binding site for FLDR redox partner flavodoxin, have been mutated to alanine. These mutant enzymes have been characterised by pre-steady-state and steady-state kinetics, UV-Vis spectrophotometry, CD and florescence. These mutants are less efficient electron transfer proteins. In a separate project it was attempted to identify genes associated with the antibiotic biosynthetic pathway of aristeromycin from Streptomyces citricolor. An aristeromycin-induced protein was isolated from S. citricolor purified to homogeneity and an N-terminal sequence was determined. From this an oligonucleotide was designed and used to probe S. citricolor chromosomal DNA. A 1000bp fragment of DNA was isolated and sequenced, and the presence of part of an ORF identified.
27
Goh, Wendy. "Studies directed towards the natural product nominine". Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/359288/.
Pełny tekst źródłaStreszczenie:
Natural product synthesis is a highly regarded and essential aspect of organic chemistry. Its challenging nature requires a wide spectrum of reactions to be performed with a broad set of skills being developed throughout each project. This thesis describes studies towards the total synthesis of nominine, an indole diterpenoid which exhibits antiinsectant properties. Synthesis of this natural product could provide entry into this family of indole diterpenoids allowing several natural products to be accessed. Chapter 1 introduces this natural product and its proposed synthetic route. Two total syntheses, by Bonjoch and Nicolaou published after this project had ceased, are also presented. Chapter 2 discusses the methods of constructing key intermediate enone 1.1 and describes its successful efficient synthesis on a multigram scale. The synthesis of natural products dehydrofukinone and fukinone using this key intermediate follows in chapter 3. Chapter 4 details the challenges and successes of the investigations towards the total synthesis of nominine. Future work for its completion and other possible related indole diterpenoids are described in chapter 5. A conclusion to the project and a chapter containing experimental details conclude this thesis.
28
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.
Pełny tekst źródła
29
Foley, Timothy Leyden. "Manipulating posttranslational modification in natural product biosynthesis". Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3390676.
Pełny tekst źródłaStreszczenie:
Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed Feb. 19, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 234-254).
30
Rodger, Robert. "Fused ring systems in natural product synthesis". Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/27645.
Pełny tekst źródłaStreszczenie:
On the instigation of A/Prof C. S. P. McErlean I investigated the rapid synthesis of fused ring compounds by a key polyene cyclisation.
Chapter 1 sets the scene by highlighting deficiencies in literature syntheses of selected fused-ring compounds, where synthetic strategies are often suboptimal. In particular, the scarcity of reported syntheses involving a direct cyclisation method is noted.
Chapter 2 discusses the taiwaniaquinoids and previous synthetic approaches including McErlean group efforts which delivered the non-natural stereochemistry. A method to produce the desired trans stereochemistry of ()-taiwaniaquinone G was developed. Attempts to apply this methodology to a divergent synthesis of the taiwaniaquinoids are detailed.
Chapter 3 extends this strategy to the attempted synthesis of compounds with a greater number of rings: the dasyscyphins, pelorol, atomarianone B and disidein. The successful partial cyclisation and subsequent full cyclisation of two farnesylarenes was reported. Larger architectures remain an elusive goal.
Chapter 4 discusses efforts in the synthesis of a different class of fused-ring compounds: the marine polycyclic ethers. The application of newer methodologies to the synthesis of the polycyclic ethers is described, however this did not lead to a viable strategy to these compounds.
31
Fernandez, Liza Sylvia. "Identification of Novel Natural Product Antimalarial Compounds". Thesis, Griffith University, 2010. http://hdl.handle.net/10072/366636.
Pełny tekst źródłaStreszczenie:
Malaria, caused by infection with the Plasmodium parasite, contributes to a significant global health burden that disproportionally affects those living in developing nations. The majority of cases are caused by infection with the species P. falciparum and P. vivax with P. falciparum being responsible for most of the ~ 1 million deaths that occur each year. There is currently no licensed malaria vaccine and while antimalarial drugs are available, the prevention and treatment of this disease has been increasingly hampered by the emergence of multidrug resistant parasites. Derivatives of the natural product artemisinin, in combination with a second antimalarial, now form the basis of antimalarial chemotherapy. Unfortunately, treatment failures of artemisinin ]based combination therapies are now emerging underscoring the need for the next generation of antimalarial compounds. Compounds derived from natural sources have the potential to provide novel antimalarial compounds as demonstrated by the isolation of artemisinin and quinine from plant species. A unique natural product extract library was, therefore, screened for antimalarial activity to identify compounds that inhibit the growth of P. falciparum. Using a standard [3H]hypoxanthine growth inhibition assay, 1773 plant and marine extracts from Australia and Papua New Guinea (PNG) were initially screened against a drug ]sensitive P. falciparum laboratory strain (3D7) at a concentration of 312.5 .ge/mL. The 210 extracts that showed >40% inhibition were then re ]screened in dose response against 3D7 and the drug ]resistant strain, Dd2, to reconfirm their activity. Extracts that showed at least 40% inhibition at the lowest dose for either strain were then tested for cytotoxicity against HeLa mammalian cells. This identified 25 plant and 30 marine extracts with selective antimalarial activity. For over 90% of these extracts, this was the first report of antimalarial activity in the literature. From these extracts the PNG plant species Flindersia amboinensis (Rutaceae), Stephania zippeliana (Menispermaceae) and Voacanga papuana (Apocynaceae) were selected for further analysis and compound isolation. Using bioassay guided fractionation, the extracts were separated over multiple steps of high ]performance liquid chromatography until pure compounds were isolated. Chemical structures were then assigned using mass spectrometry and nuclear magnetic resonance spectroscopy. The extract from F. amboinensis yielded the indole alkaloids, flinderole B, flinderole C and dimethylisoborreverine. These were structural analogues of flinderole A and isoborreverine previously isolated from F. acuminata. The flinderole indole alkaloids were also shown to be novel structures. The remaining extracts yielded known antimalarial compounds, specifically liriodenine and xylopine from S. zippeliana and voacamine from V. papuana. Antimalarial activity had not been previously reported for the Flindersia indole alkaloids. To elucidate the potency and selectivity of these isolated compounds, they were then screened against a panel of P. falciparum strains exhibiting different levels of drug sensitivity, along with the mammalian cell lines, HeLa and HEK ]293. The indole alkaloids isolated from Flindersia showed the most selectivity and potency, with IC50 values between 0.02 . 1.61 .M. In particular the compounds containing a dimethylated ethylamine side chains also showed greater activity against the chloroquine resistant strains. The remaining compounds all showed IC50 values > 1 .M, however, xylopine did show comparable selectivity to the flinderole class of compounds. The antiparasitic activity of these compounds was also further explored by screening for inhibitory activity against Trypanosoma brucei brucei. All compounds, however, were less active against this organism. To further understand the effect of the Flindersia alkaloids on P. falciparum, in vitro growth inhibition studies were carried out using parasite cultures at the different asexual growth stages, which are associated with different molecular targets. Treatment of ring, trophozoite or schizont ]stage parasites with dimethylisoborrevine or flinderole B for 6 h, showed that over a growth period of 24 h, trophozoite stages were more susceptible to these compounds than ring or schizont stages. Morphological analysis by light and electron microscopy of compound treated parasites showed abnormalities of the food vacuole, the organelle used for the storage of haemozoin, a by ]product of haemoglobin degradation. The disruption of haemoglobin degradation and the subsequent detoxification of the toxic haem moiety to the inert haemozoin is a well characterised molecular target. However, using an in vitro assay the latter process was found to be not affected by either dimethylisoborreverine or flinderole B, suggesting another target is involved. Isobologram analysis also showed antagonistic interactions between dimethylisoborreverine and flinderole B when used in combination with mefloquine and artemisinin. Overall the novel activity of the Flindersia alkaloids warrants further work to explore the potential of these compounds as antimalarial agents.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Eskitis Institute for Cell and Molecular Therapies
Science, Environment, Engineering and Technology
Full Text
32
Heberlig, Graham William. "Harnessing Natural Product Biosynthesis to Access Macrocycles". Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39260.
Pełny tekst źródłaStreszczenie:
Macrocyclic natural products are conformationally restricted molecules that often have improved ability to bind with high affinity and selectivity on a target. Within macrocycle chemistry, macrolactone formation is a particularly challenging transformation and has spurred the development of highly diverse synthetic strategies. A key strategy that is missing is a chemoenzymatic approach to this challenge, and the logical place to look for such a catalyst is the thioesterases (TEs) from the biosynthetic pathways that generate these molecules in Nature. These TEs are α/β-hydrolases containing an active site serine or cysteine and a conserved histidine/aspartate catalytic diad. The research presented here describes the development of two related TE domains from resorcylic acid lactone polyketide synthases found in various fungi. Unlike their bacterial counterparts these macrocyclization catalysts have proven to be stereotolerant with regard to the secondary alcohols involved in macrocyclization. Further work has demonstrated that they are also amenable to generating 12- to 18-member macrolactones. These TE domains can also catalyze macrolactam and cyclic depsipeptide formation, setting the stage for these enzymes to serve as a platform for catalyst development. The development of 2,3-diaminopropionate (DAP) incorporation in place of the active site Ser to trap acyl-enzyme intermediates was used to structurally characterize the formation of a macrocyclic trimer. This technique will be broadly applicable to characterizing other TEs. Overall the research presented here lays the foundation for the long term development of TEs as macrocyclization biocatalysts.
33
Angell, Scott Edward. "Genomic and metagenomic approaches to natural product chemistry". [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-2671.
Pełny tekst źródła
34
Hutchinson, John Howard. "The use of camphor in natural product synthesis". Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/25830.
Pełny tekst źródłaStreszczenie:
(+)-9,10-Dibromocamphor 3̲7̲, prepared in three steps from (+)-3-e̲n̲d̲o̲-bromocamphor 1̲5̲a̲, was found to undergo facile ring cleavage to provide the cyclopentanoid ring systems 1̲5̲8̲, 1̲5̲9̲ and 1̲6̲1̲. The bromoacid 1̲5̲9̲ was readily lactonised to provide 1̲6̲0̲ in high yield.
The hydroxyacid 1̲6̲1̲ was converted into the hydrindenone 1̲9̲0̲ in three steps and a further six steps were required to complete the total enantiospecific synthesis of (-)-estrone e̲n̲t̲4̲1̲.
Studies directed toward the synthesis of vitamin D₃ (2̲1̲3̲) and metabolites have shown that diastereoselective alkylation of lactone 1̲6̲0̲ and ester 2̲8̲3̲ (derived from 1̲6̲1̲) can be accomplished in high yield and with almost complete stereoselectivity. As a result, diol 3̲2̲2̲, representing the structural sub-unit of ring D and side chain of vitamin D₃, has been synthesised.
Ring cleavage of the bromoketone 3̲5̲0̲ (derived from 1̲5̲9̲) gave 3̲5̲2̲ which was transformed into the aldehyde 3̲3̲2̲ and the trienols 3̲4̲0̲a̲ and 3̲4̲0̲b̲ to complete a formal synthesis of 3̲2̲7̲a̲, one of the components of the California Red Scale pheromone.
Methylation of camphor 1̲0̲ yielded the 3-e̲x̲o̲-methyI derivative 3̲6̲2̲b̲ as the major product. The thermodynamically most stable epimer was found to be 3-e̲n̲d̲o̲-methylcamphor 3̲6̲2̲a̲. In contrast, 3-methylcamphor 3̲6̲2̲a.̲b̲ undergoes preferential endo alkylation. The factors governing these results are discussed. (+)-3- e̲n̲d̲o̲-Bromocamphor 1̲5̲a̲ and (+)-3- e̲n̲d̲o̲-9-dibromocamphor 1̲8̲a̲ were found to rearrange to provide (-)-6- e̲n̲d̲o̲-bromocamphor 1̲7̲2̲ and (-)-6- e̲n̲d̲o̲-9-dibromocamphor 2̲6̲. Dehalogenation of 1̲7̲2̲ provided optically pure (-)-camphor e̲n̲t̲1̲0̲ while dehydrohalogenation gave (+)-5,6-dehydrocamphor 1̲7̲3̲.[formula omitted]Science, Faculty of
Chemistry, Department of
Graduate
35
Dias, Daniel Anthony, i danieldias@iprimus com au. "Natural Product Studies of Terrestrial and Marine Organisms". RMIT University. Applied Sciences, 2009. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20091019.161302.
Pełny tekst źródłaStreszczenie:
This thesis describes the isolation and structure elucidation of ten novel secondary metabolites from one fungus (Pycnoporus cinnabarinus), four lichens (Chrysothrix xanthina, Candelaria concolor, Ramalina glaucescens and Xanthoria parietina), three algae (Plocamium mertensii, Laurencia filiformis and Laurencia elata), two plants (Haemodorum simplex and Dianella callicarpa) and one sponge (Dactylospongia sp). The structures of these isolated compounds were elucidated by a combination of spectroscopic and chemical methods. This thesis also reports two new crystal structures, the identification of two new methylsilylated derivatives as well as the isolation of thirty seven previously reported compounds in which the complete structural assignment by one and two dimensional nuclear magnetic resonance spectroscopy (NMR) has been carried out on known compounds with incomplete or no NMR spectroscopic data. Furthermore, detailed spectroscopic analyses resulted in the re assignment of 1H and 13C chemical shifts for several previously isolated natural products. The biological screening (antimicrobial, antiviral and antitumor assays) of crude extracts and isolated natural products has also been presented. The application of chemical profiling techniques including GCxGC and high pressure liquid chromatography-nuclear magnetic resonance (HPLC-NMR) were utilised to assist with the natural product dereplication process (chemical profiling), monitor chemical degradations in situ and to identify the presence of new natural products and artefacts. In total, fifteen separate terrestrial and marine organisms were investigated.
36
Nodwell, Matthew B. "Synthesis of biologically active marine natural product analogues". Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/25745.
Pełny tekst źródłaStreszczenie:
Natural products have long been a source of inspiration for many drugs in human use. The Andersen lab examines compounds from marine sources that can be used as lead structures for drug discovery. Synthetic studies, structure-activity relationships (SAR) and biological findings of two such compounds are described in this thesis.
The first is pelorol, a meroterpene isolated from a tropical sponge Dactylospongia elegans. Pelorol is a small molecule activator of SHIP 1, a phosphatase that is a negative regulator of the P13K pathway in hematopoetic cells. Using a synthetic route from a previous co-worker, Lu Yang, a series of SHIP 1 activating compounds based on pelorol were synthesized. These compounds were evaluated for selectivity, potency, and efficacy in a series of biological studies, leading to the discovery of 2.27 as a preclinical lead compound. Water-soluble prodrugs of the SHIP 1-activating compounds were also synthesized and their properties reported.
The second compound examined is ceratamine A, an alkaloid isolated from the sponge Pseudoceratina sp. from Papua New Guinea. Ceratamines A and B are microtubule stabilizing antimitotic agents that may be useful in cancer chemotherapy. The core imidazo[4,5,d]azepine heterocycle of the ceratamines has no precedent among known synthetic or natural compounds. The relatively simple structure of the ceratamines and the novel antimitotic phenotype they generate makes them attractive targets. Desbromo ceratamine A (3.44) was synthesized by an efficient and scaleable route, confirming the structure of ceratamine A and validating the biological activity of the core pharmacophore. Synthetic efforts towards ceratamine A were ultimately thwarted by the inability to install the bromine atoms present in the natural product. A significant finding is that the bromine atoms in ceratamine A contribute significantly to the antimitotic potency of the compound necessitating a bioisosteric approach to more potent antimitotic ceratamine-based agents.
37
Flasz, Jakub Tadeusz. "Total synthesis of the antitumour natural product, (-)- echinosporin". Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.601477.
Pełny tekst źródłaStreszczenie:
The following dissertation describes a collection of results that led to a successful formal total synthesis of a naturally-occurring antitumour antibiotic, (-)..echinosporin. To achieve that, various synthetic strategies were developed and examined, all of which relied on a cycloadditive event as a key step to prepare the [3.4.0J-bicyclic framework of (-)-echinosporin. The synthesis was eventually accomplished using the Padwa [3+2] cycloaddition-elimination of allenylphenylsulphone to a chiral sugar enone 6 as a key transformation. it provided the first recorded example of this reaction used in complex natural product total synthesis. Following a series of functional group interconversions on this cycloadduct, a mild new method for the C-carboxyalkylation of bromomagnesium ketone enolates was applied to install the C(11)~carboxylic group of (-)- echinosporin. The quaternary OH-bearing stereocentre was introduced via a substrate~directed osmylative dihydroxylation on a i3-keto ester enol 71 . The resulting ketone 77 was advanced into 70 via Barton deoxygenation. Following that, the crucial C(8)-C(9) unsaturation was introduced starting from the ketone 70 through a three-step sequence based on the Barton vinyl iodide synthesis and Pd(O)-mediated dehalogenation. Next, a TEMPO-based oxidation was used to bring the C(10)- position to a correct oxidation state. Following protection as the allyl ester, an E1cb silyloxy elimination installed the remaining C(4)-C(5) unsaturation. The allyl ester 90 was finally transformed into a primary amide and the C-2 ethyl glycoside was chemoselectively hydrolysed using aqueous HBF4 to reveal Smith's intermediate 1.
38
Foot, Jonathan Stuart. "New synthetic methodology and antiviral natural product synthesis". Thesis, University of York, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412621.
Pełny tekst źródła
39
Barry, Conor. "Clavosolide A : Prins cyclisation in natural product synthesis". Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413614.
Pełny tekst źródła
40
Chrobak, Olga Maria. "Approaches to natural product antibiotic discovery from actinomycetes". Thesis, University of Newcastle upon Tyne, 2018. http://hdl.handle.net/10443/3992.
Pełny tekst źródłaStreszczenie:
The problem of increasing emergence of antibiotic resistance coupled to a decrease in the discovery rate of new antibiotics has been recognised as a worldwide health threat. One of the solutions to this problem is discovery of novel antibiotics and new antibiotic classes. Natural product (NP) antibiotic discovery from actinomycetes is a well-established approach which yielded many clinically relevant drugs and has received an increasing interest in the recent years due to modern technological advancements. This study was set out to investigate several approaches to NP antibiotic discovery from actinomycetes with the aim to identify the success rate of each, propose a new approach and potentially discover novel NP antibiotics. In chapters 3 and 4, the Waksman platform to NP antibiotic discovery was investigated, enhanced with bioactivity dereplication screens against multi-drug resistant (MDR) bacteria and selection of taxonomically novel Streptomyces spp. Although the process proved time- consuming and yielded known compounds, two putatively new derivatives from a known antibiotic class of streptophenazines (produced by strain DEM20663) were identified. In chapter 5 genome analysis of DEM20663 focusing on biosynthetic gene clusters (BGCs) responsible for the antibiotic activity identified in the previous chapters was performed. Two previously uncharacterised BGCs encoding a type II PKS and a phenazine derived NP antibiotics were identified. Based on the genomic data, the biosynthetic pathways for both groups of compounds were suggested and the structures of two putatively novel streptophenazine derivatives were proposed. Heterologous expression of two orphan BGCs as predicted by bioinformatic analysis was discussed in chapter 6. With no a priori knowledge of the resulting NPs, the attempts to express two BGCs from a novel Amycolatopsis sp. in Streptomyces coelicolor M1152 and M1154 hosts resulted in purification of a putatively novel NP of a BGC encoding an iterative type I polyketide synthase. In chapter 7 an integrated “omics” approach to NP antibiotic discovery was proposed. Based on integrating data from genomic, transcriptomic and metabolomic studies fifteen prioritised actinomycete strains were examined. Although this resulted in a number of known NP antibiotics, a putatively novel lantibiotic was identified using the integrated “omics” approach.
41
Yu, Miao. "Stereoselective Olefin Metathesis Reactions for Natural Product Synthesis". Thesis, Boston College, 2014. http://hdl.handle.net/2345/3861.
Pełny tekst źródłaStreszczenie:
Thesis advisor: Amir H. HoveydaChapter 1. The first examples of highly Z- and enantioselective ring-opening/cross-metathesis reactions are disclosed. Transformations involve meso cyclic olefin substrate and styrenes or enol ethers as olefin cross partners. A stereogenic-at-Mo monoaryloxide monopyrrolide (MAP) complex, prepared and used in situ, is discovered for the efficient formation of Z olefins. Such complex, bearing a relatively smaller adamantylimido and a larger chiral aryloxide ligand, leads to kinetic Z-selectivity due to the size differential. In most cases, the resulting disubstituted Z olefins are formed with excellent stereoselectivity (>95% Z). Chapter 2. The protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Stereoselective cyclizations are performed with either Mo- or W-based monoaryloxide monopyrrolide (MAP) complex at 22 oC. Synthetic utility of such broadly applicable transformation is demonstrated by synthesis of several macrocyclic natural products: relatively simpler molecules such as epilachnene (91% Z) and ambrettolide (91% Z), as well as advanced precursors to epothilones C and A (97% Z) and nakadomarin A (94% Z). Several principles of catalytic stereoselective olefin metathesis reactions are summarized based on the studies: 1) Mo-based catalysts are capable of delivering high activity but can be more prone to post-RCM isomerization. 2) W-based catalysts, though furnish lower activity, are less likely to cause the loss of kinetic Z selectivity by isomerization. 3) Reaction time is critical for retaining the stereoselectivity gained from kinetic, which not only applicable with MAP complexes but potentially with other complexes as well. 4) By using W-based catalyst, polycyclic alkenes can be accessed with sequential RCM reactions, without significant erosion of the existing Z olefins in the molecule. Chapter 3. An enantioselective total synthesis of anti-proliferative agent (+)-neopeltolide is presented. The total synthesis is accomplished in 11 steps for the longest linear sequence and 28 steps in total, including 8 catalytic reactions. Particularly, several Mo- or Ru-catalyzed stereoselective olefin metathesis reactions as well as N-hetereocyclic carbene (NHC)-catalyzed enantioselective boron conjugate addition to an acyclic enoate have proven to be effective for convergent construction of the molecule. The most important novelty of the study incorporates the explorations of feasibility of Z-selective cross-metathesis reactions to solve the challenge of installing two Z olefins with excellent selectivity
Thesis (PhD) — Boston College, 2014
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
42
Yu, Elsie. "Catalytic Stereoselective Olefin Metathesis for Natural Product Synthesis". Thesis, Boston College, 2018. http://hdl.handle.net/2345/bc-ir:107714.
Pełny tekst źródłaStreszczenie:
Thesis advisor: Amir H. HoveydaChapter 1. Efficient Z-Selective Synthesis of Allylic- and Alkenyl Boronates by Catalytic Cross-Metathesis Efficient Z-selective cross-metathesis reactions to furnish Z-(pinacolato)-allylboron and Z-(pinacolato)alkenylboron compounds through catalytic cross-metathesis are disclosed. Z-allylic boron compounds are generated by the use of catalytic amounts of a W-based monoaryloxide monopyrrolide (MAP) complex in up to 91% yield and 96:4 dr after allylation to benzaldehyde. Alkenylboron compounds are prepared in high yields and high Z selectivity in up to 93% yield and 97:3 Z:E. Cross-metathesis reactions with 1,3-dienes and aryl olefins are efficient and highly Z-selective. Combination of cross-metathesis and cross-coupling to synthesize anticancer agent combretastatin A-4 highlights the utility of this approach. Chapter 2. Synthesis of Macrocyclic and Acyclic Z-Enoates and (E,Z) or (Z,E) Dienoates by Catalytic Cross-Metathesis The first examples of kinetically controlled catalytic olefin metathesis reactions to generate Z-α,β-unsaturated macrocyclic and acyclic esters are disclosed. The synthesis of (E,Z) or (Z,E)-dienoates are also presented. Reactions promoted by 3.0–10 mol % of Mo-based monoaryloxide monopyrrolide complex proceed to completion to the desired macrocycles within 2–6 h at room temperature. Macrocycles of diverse ring sizes are formed in 79:21 to >98:2 Z:E selectivity. Pure Z isomers can be obtained after purification in up to 75% yield. Acyclic Z-α,β-unsaturated esters are prepared in the presence of acetonitrile to avoid using excess amounts of the more valuable cross-partner substrate. Spectroscopic investigations and X-ray analysis rationalize the positive effect of acetonitrile in the reaction system. Linear (Z)-enoates are generated in up to 71% yield and up to >98:2 Z:E. (E,Z)-Dienoates are generated with high Z selectivity as well. The utility of the ring-closing metathesis and cross-metathesis is highlighted by the synthesis of an (+)-aspicilin precursor and the C1–C12 fragment of biologically active natural product (–)-laulimalide. Chapter 3. Application of E-Selective Catalytic Ring-Closing Metathesis in the Total Synthesis of Dolabelides A, B, C and D Efforts towards the enantioselective synthesis of the dolabelide family of anti-cancer macrolides is presented. Development of a total synthesis incorporating a late-stage kinetically E-selective RCM is illustrated. Previous attempts to synthesize the macrolide by ring-closing metathesis (RCM) have demonstrated poor efficiency and low selectivity for the E isomer. Methodology developed in our group with acyclic trisubstituted cross-metathesis demonstrates that high selectivity can be achieved with stereodefined 1,2-disubstituted and trisubstituted olefins by the use of the proper catalyst and reaction design. Modern catalytic and stereoselective approaches towards the two main fragments of dolabelide are presented. More efficient and concise routes will be pursued to highlight the utility of the proposed disconnections and practicality of the total synthesis
Thesis (PhD) — Boston College, 2018
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
43
O'Sullivan, Paul Thomas. "Natural product systems from eight-membered ring lactones". Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621632.
Pełny tekst źródła
44
Wang, Xiaoling. "Natural product discovery and biosynthesis from soil actinobacteria". Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=203796.
Pełny tekst źródłaStreszczenie:
New structurally diverse natural products can be discovered when carefully designed screening procedures have been applied and when a prolific organism from a different biological source is examined, such as, rare actinobacteria from an untapped environment. Chapter 3 describes the isolation and structure characterisation of eight compounds from the rare actinobacterum, Saccharothrix xinjiangensis (NRRL B-24321), including, two new 16-member macrolides, Tianchimycin A and B, respectively. OSMAC (One Strain - Many Compounds) is used to search bioactive compounds from the metabolic profile of S. xinjiangensis, isolated from a semi-arid or desert area, Tanchi, Xinjiang in the study. Isolated compounds were characterised by NMR spectroscopy and accurate mass spectrometric analysis. Investigations of the natural products at all levels, from genes, to enzymes, to molecules has revealed insights into differentiating features of the biosynthetic pathways that lead to structural diversity of natural products. The presence of a halogen substituent in natural products profoundly influences their biology activity. Actinomycins are a well-known class of antibiotics/anticancer agents. Here, the gene cluster directing chlorinated actinomycin G biosynthesis in Streptomyces iakyrus (DSM 41873) has been identified and sequenced. It contains one actinomycin synthetase I (ACMS I) gene and two copies of ACMS II and III genes. Genetic analysis demonstrates a unique partnership between the putative hydroxylation and chlorination activities as both acm8 and acm9 genes need to be transcribed for the biosynthesis of actinomycin G2 and actinomycin G3, respectively. In chapter 5, I descries a possible metabolic flux rebalancing pathway for increasing phenazinomycin production in S. iakyrus (DSM 41873) after interruption of the methyltrasfer gene (acmG5') in actinomycin G gene cluster. The gene cluster of phenazinomycin was identified by in silico analysis and by comparison with a known phenazine gene cluster from S. iakyrus (DSM 41873).
45
Zou, Da-ming, Molly Brewer, Francisco Garcia, Jean Feugang, Jian Wang, Roungyu Zang, Huaguang Liu i Changping Zou. "Cactus pear: a natural product in cancer chemoprevention". BioMed Central, 2005. http://hdl.handle.net/10150/610227.
Pełny tekst źródłaStreszczenie:
BACKGROUND:Cancer chemoprevention is a new approach in cancer prevention, in which chemical agents are used to prevent cancer in normal and/or high-risk populations. Although chemoprevention has shown promise in some epithelial cancers, currently available preventive agents are limited and the agents are costly, generally with side effects. Natural products, such as grape seed, green tea, and certain herbs have demonstrated anti-cancer effects. To find a natural product that can be used in chemoprevention of cancer, we tested Arizona cactus fruit solution, the aqueous extracts of cactus pear, for its anti-cancer effects in cultured cells and in an animal model.METHOD:Aqueous extracts of cactus pear were used to treat immortalized ovarian and cervical epithelial cells, as well as ovarian, cervical, and bladder cancer cells. Aqueous extracts of cactus pear were used at six concentrations (0, 0.5, 1, 5, 10 or 25%) to treat cells for 1, 3, or 5 days. Growth inhibition, apoptosis induction, and cell cycle changes were analyzed in the cultured cellsthe suppression of tumor growth in nude mice was evaluated and compared with the effect of a synthetic retinoid N-(4-hydroxyphernyl) retinamide (4-HPR), which is currently used as a chemoprevention agent. Immunohistochemistry staining of tissue samples from animal tumors was performed to examine the gene expression.RESULTS:Cells exposed to cactus pear extracts had a significant increase in apoptosis and growth inhibition in both immortalized epithelial cells and cancer cells in a dose- and time-dependent manner. It also affected cell cycle of cancer cells by increasing G1 and decreasing G2 and S phases. Both 4-HPR and cactus pear extracts significantly suppressed tumor growth in nude mice, increased annexin IV expression, and decreased VEGF expression.CONCLUSION:Arizona cactus pear extracts effectively inhibited cell growth in several different immortalized and cancer cell cultures, suppressed tumor growth in nude mice, and modulated expression of tumor-related genes. These effects were comparable with those caused by a synthetic retinoid currently used in chemoprevention trials. The mechanism of the anti-cancer effects of cactus pear extracts needs to be further studied.
46
Andong, Koung Edzidzi Ursula-Claire. "Natural product derivative activates autophagy in cancer cells". Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/24489.
Pełny tekst źródłaStreszczenie:
Artemisinin, a natural product and its derivatives are potent antimalarial compounds, which have shown anticancer activity. In this study, we further characterized a novel artemisinin derivative namely EXP57EA which was previously designed and synthesized by the Chemistry Department at the University Of Cape Town. We determined the effect of EXP57EA on a panel of cancer cell lines, characterized the mode of cell death and also performed preliminary investigations of the signaling pathways that trigger the mode of cell death. Dihydroartemisinin (DHA), EXP57EA and cisplatin were screened on a selected panel of cancer cell lines: 3 esophageal cancer cell lines WHCO1, WHCO5, KYSE150; one breast cancer cell line MDA-MB-231 and one cervical cancer cell line SiHa. The 3-[4, 5-dimethylthiazol-2-yl]-2, 5- diphenyltetrazolium bromide (MTT) assay, and analysis with GraphPad prism software were used to calculate IC₅₀ values. EXP57EA displayed toxicity in the panel of cancer cell lines studied, and had lower IC₅₀ values (IC₅₀ values were ranging from 15.8 μM to 25.1 μM) than DHA and cisplatin. DHA was only active in two cells lines: WHCO1 (21.3 μM) and WHCO5 (77.3 μM), IC₅₀ values of cisplatin were ranging from 31.2 μM to 108.1 μM. EXP57EA was further investigated to understand the mode of cell death activated in the panel of cancer cell lines. The results showed that EXP57EA did not induce apoptosis in any of the cell lines studied, whereas DHA induced apoptosis, based on the PARP cleavage assay. In contrast, treatment with EXP57EA induced the appearance of vacuoles in treated cells compared to untreated cells, which was suggestive of autophagy. Autophagy was monitored by analyzing the expression level of two autophagy markers, Beclin1 and LC3-II by western blot. It was observed that EXP57EA treatment caused changes in the expression levels of both Beclin1 and LC3-II. We showed that EXP57EA induced elevated levels of autophagy, based on an increase in the flux of autophagy in the treated cells, since the lysosomal inhibitors ammonium chloride (NH₄Cl) and chloroquine substantially blocked LC3-II turnover in WHCO1 (confirmed previous result in our laboratory) and SiHa cancer cell lines. Furthermore, we also showed that treatment with EXP57EA resulted in increased expression of CHOP (by Real-Time PCR), and activated the PERK/eIF2α pathway, since treatment of WHCO1 cells with EXP57EA stimulated phosphorylation of eIF2α, suggesting that ER stress might be involved in mediating EXP57EA-induced cell death. Our results also suggested that EXP57EA activated the JNK pathway since treatment of WHCO1 and WHCO5 cells with EXP57EA stimulated phosphorylation of cjun and resulted in elevated levels of total c-jun. These results suggested the JNK pathway might also be involved in EXP57EA-induced cell death. However, the proposed involvement of the PERK/eIF2α pathway and the JNK pathway in EXP57EA-mediated autophagy is of a preliminary nature, and further work will have to be done to confirm the involvement of these pathways. This study showed that EXP57EA may have potential as an anticancer drug lead.
47
Giampa, Geoffrey. "Investigations Into Carbon Nanotube And Natural Product Synthesis". ScholarWorks @ UVM, 2016. http://scholarworks.uvm.edu/graddis/552.
Pełny tekst źródłaStreszczenie:
This dissertation describes research into the synthesis of carbon nanotubes using traditional organic synthetic methods, as well as work on the fragmentation of β-hydroxy-α-diazoesters with a γ-hetero group and applications of their reactivity towards natural product synthesis.
Carbon nanotubes are unique structures that can exhibit different electronic properties based on their chiral vector, and are a potential future source of semiconductors. Current methods of synthesis are unable to be adapted to commercial synthesis, providing the opportunity for the application of organic synthetic methods to generate them more uniformly and on a larger scale.
The generation of tethered aldehyde ynoates and their utilization in 1,3-dipolar cycloadditions has been well developed by the Brewer group. Traditionally they have been generated from γ-siloxy-β-hydroxy-α-diazoesters, herein we explore utilizing an amino group as the fragmentation initializer. Additionally, application of the tethered aldehyde ynoate towards the synthesis of the natural products Demissidine and Aspidospermine are discussed.
48
Messer, Roland. "Natural product-like compound libraries from D-(-) ribose /". [S.l.] : [s.n.], 2005. http://www.zb.unibe.ch/download/eldiss/05messer_r.pdf.
Pełny tekst źródła
49
Wang, Dongdong. "Natural Product Chemical Probe Discovery against Parkinson’s Disease". Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367616.
Pełny tekst źródłaStreszczenie:
Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting over five million patients worldwide. Like Alzheimer’s disease (AD), it mostly affects the elderly and causes considerable disability and suffering. Unfortunately, the molecular mechanism of PD is still poorly understood, and there are no drugs available to treat the disease. Our overall aim was to identify natural products to probe PD by phenotypic assay using human olfactory neurosphere-derived (hONS) cells from PD patients. The research presented in this thesis exemplifies the importance of natural products as chemical probes for further investigation of PD as well as lead compounds for future PD-drug development.
The thesis begins with an introduction of PD and the chemotherapeutics for PD. It also covers a review on the natural origin anti-PD compounds and the analysis of their physicochemical properties using Lipinski’s rule of five. As part of a research program aiming to identify anti-PD chemical probes, a high throughput screening assay was developed to screen 4224 fractions. Twenty fractions were confirmed to display neuroprotective effects of the PD cells against rotenone. Seven prioritized fractions, representing one Australian marine sponge Jaspis splendens (subject 1) and two Australian terrestrial plants Gloriosa superba (subject 2) and Alangium villosum (subject 3), were selected for large scale extraction and isolation. The results were presented in Chapter 2 to 5.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
Full Text
50
Salem, Shaimaa Mohamed. "Biosynthesis of Marineosin, a Spiroaminal Undecylprodiginine Natural Product". PDXScholar, 2012. https://pdxscholar.library.pdx.edu/open_access_etds/936.
Pełny tekst źródłaStreszczenie:
Marineosins A and B are two spiroaminal-ring containing tripyrrole compounds isolated from the marine actinomycete, Streptomyces CNQ-617, and were found to possess potent and selective cytotoxic activity against leukemia and melanoma. Marineosins belong to the prodiginines class of natural products, examples of which are undecylprodiginine and streptorubin B. Unlike marineosins, prodiginines structures are characterized by the presence of fully conjugated tripyrrole nucleus linked to an alkyl chain (that lacks any oxygen). Cyclic prodiginines arise from an oxidative cyclization of the alkyl chain onto the tripyrrole, a step catalyzed by Rieske-oxygenase like enzymes such as RedG. The biosynthesis of prodiginines is directed via the red gene cluster. The unique structural differences between marineosin and other prodiginines spurred the proposal of a number of hypotheses for its biosynthesis, none of which have been experimentally tested. A red gene cluster homolog which has only one extra dehydratase-encoding gene; marA has been identified from the genomic library of Streptomyces CNQ-617, and the identified cluster was proposed to direct the biosynthesis of marineosin. In this study, the identified putative gene cluster was expressed in the heterologous host, S. venezuelae, and marineosin production in the new strain; JND2 was confirmed via LC/MS and 1H-NMR. The new engineered strain also produces a myriad of marineosin related shunt metabolites and pathway intermediates. This study hence presents the first identified gene cluster proved to direct the biosynthesis of marineosin; the mar gene cluster and proves that the cloned cluster encodes most, if not all the enzymes required to direct the biosynthesis of marineosin. Deletion of the Rieske-oxygenase encoding gene; marG (a RedG homolog) from the mar gene cluster led to the accumulation of 2-hydroxyundecylprodiginine; G410 with an m/z 410.28 and molecular formula C25H35O2N3. This data proves that MarG is not responsible for the introduction of the spiromaminal ring oxygen on the alkyl chain, but is required for catalyzing macrocyclic ring formation between C-8 and C-9 of G410. Undecylprodiginine production in marG deletion mutant was not observed which indicates that undecylprodiginine is likely not an intermediate along the pathway for marineosin biosynthesis, and indicates that the spiroaminal ring oxygen is introduced early in the pathway, possibly due to the incorporation of a 3-hydroxy-butyric acid starter unit. Deletion of the dehydratase-encoding gene; marA, from the mar gene cluster led to the accumulation of compounds JN408 and JN422 with m/z 408.26 and 422.24 and molecular formulae C25H33O2N3, and C25H31O3N3, respectively. Purification and structure elucidation of JN408 proves it to be an oxidized marineosin analog which has fully aromatic tripyrrole rings while; purification and structure elucidation of JN422 proves it to be a 9-keto-JN408 derivative. Both JN408 and JN422 compounds have a spiroaminal ring which indicates that MarA does not catalyze spiroaminal ring formation but catalyzes the reduction of pyrrole ring B of JN408 to yield marineosin. Therefore, we are proposing that MarA acts as a dehydrogenase, rather than a dehydratase. We are proposing that the intramolecular spiroaminal ring formation is catalyzed by either MarG or occurs non-enzymatically. JN422 is a shunt metabolite produced due to promiscuous activity of either MarG or an unidentified oxidase in the mar cluster, possibly MarT. From the data generated in this study, we present the first experimentally supported pathway for the biosynthesis of marineosin and the opportunity to generate novel compounds with potentially useful biological activities.