Dissertations / Theses on the topic 'Natural products'

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.

Pashoo es una empresa que se creó gracias a la idea de cinco estudiantes que se encuentran cursando el décimo ciclo en la Universidad Peruana de Ciencias Aplicadas (UPC), la cual está orientada a la industria de cuidado de belleza y salud mediante la fabricación y comercialización de shampoo en barra 100% naturales a base de ingredientes seleccionados de acuerdo con sus valores nutricionales que estos le brindan al cabello. Contamos con shampoos de distintos olores y para todo tipo de cabellos como por ejemplo shampoo a base de aceite de jojoba, coco, almendras, argán y palta combinados con esencias naturales que le brindan al cliente una sensación de relajación. Por otro lado, hemos segmentado a nuestros clientes de manera que nuestro producto pueda solucionar sus problemas. Para este proyecto, nos estamos fijando en las mujeres que tienen problemas de caída de cabello e irritación en el cuero cabelludo y que estén buscando productos orgánicos y naturales que tengan conciencia sobre el cuidado del medio ambiente. Vamos a distribuir nuestros productos mediante ferias y por delivery utilizando como canales de comunicación las redes sociales y nuestra página web en donde los clientes podrán encontrar información necesaria sobre nosotros y nuestros productos. De la misma forma, mostrar las validaciones del modelo de negocio, el desarrollo del negocio, el plan financiero y de marketing, así como las operaciones que se realizaron a lo largo de este proyecto dejando por último nuestras conclusiones y recomendaciones por la realización del proyecto de negocio.
Pashoo is a company that was created thanks to the idea of five students who are studying the tenth cycle at the Universidad Peruana de Ciencias Aplicadas (UPC), which is oriented to the beauty and health care industry through manufacturing and marketing 100% natural bar shampoo based on selected ingredients according to their nutritional values that they provide to the hair. We have shampoos of different scents and for all types of hair such as jojoba oil, coconut, almond, argan and avocado shampoo combined with natural essences that give the client a feeling of relaxation. On the other hand, we have segmented our customers so that our product can solve their problems. For this project, we are looking at women who have problems with hair loss and irritation on the scalp and who are looking for organic and natural products that are aware of the care of the environment. We will distribute our products through fairs and by delivery using social media and our webpage as communication channels where customers can find necessary information about us and our products. In the same way, show the validations of the business model, the development of the business, the financial and marketing plan, as well as the operations that were carried out throughout this project, finally leaving our conclusions and recommendations for the completion of the project of business.
Trabajo de investigación

Montbretins A-E were isolated from the corms of Crocosmia sp., an invasive perennial plant. The montbretins are inhibitors of human pancreatic α-amylase (HPA). Montbretin A (2- 30) is a competitive inhibitor of HPA with a K₁ of 1.3 nM. The activity of the other family members varied significantly and provided structure-activity information. Saturation Transfer Difference (STD) NMR spectroscopy was used to determine that the caffeic acid region of the montbretins is important for binding. HPA is involved in the breakdown of complex carbohydrates; inhibition of this enzyme could help with regulation of blood sugar levels after a meal. In the lungs of cystic fibrosis patients, the activation of Toll-Like Receptor 5 (TLR5) in the presence of flagellin leads to inflammation and obstruction. Girolline (3-1), a known alkaloid, was isolated from a Phonpeian sponge following potent inhibition of the flagellin initiated TLR5 activation. No activity was observed in any synthetic analogues of girolline. The massacreones are a new family of ecdysteroids isolated from an unidentified Dominican cnidarian. The extract of the cnidarian had good TLR5 activity, but the massacreones – namely massacreone A (3-25) and massacreone B (3-26) have only moderate activity and a small window of activity before they are toxic. The algal pigment caulerpin (4-29) was isolated from Caulerpa sp. as a compound showing good activity in a yeast growth restoration assay designed to identify inhibitors ofhuman indoleamine-2,3-dioxygenase (IDO). Caulerpin did not show any activity in a free enzyme IDO assay. IDO is involved in immune escape, which prevents the immunological rejection of tumors.

The chemical exploration of extracts from cultures of the marine bacterial isolate PNG-276 yielded the novel antibiotic tauramamide (2.13), a non-ribosomal peptide active against cultures of Enterococcus sp. and methicillin-resistant Staphylococcus aureus (MRSA). A study of extracts of the marine sponge Spirastrella coccinea yielded the novel macrolide methylspirastrellolide C (3.14), which is active against protein phosphatase 2A (PP2A). A third study examined sponge extracts active in a cannabinoid receptor assay, yielding two known compounds, an A- nor -steroid derivative (4.10) and bengamide A (4.11). Neither purified compound was active in the cannabinoid receptor assay, although in both cases this is the first report of these compounds being isolated from Stylissa massa and Hemiasterella aff. affinis sponges, respectively. [See Thesis for Diagrams]
Science, Faculty of
Chemistry, Department of
Graduate

The first chapter of this thesis deals with some substitution reactions of -carbolines aimed at the synthesis of the metabolite 6-hydroxyharmine which is produced when harmine is incubated with rat liver microsomes. The conversion of 6-bromo- and 6-nitro-harmine into its hydroxy-analogue was not achieved but direct hydroxylation of harmine using lead tetra-acetate trifluoroacetic acid followed by in situ reduction with zinc dust gave 6-hydroxyharmine. This reaction also worked with harman and norharman. In the second chapter, the synthesis of 4-aryl-5,2'-oxido-coumarins has been carried out by oxidative coupling, using dichloro-dicyanobenzo-quinone or potassium ferricyanide on methoxy- or hydroxy-4-phenylcoumarins. Our synthesis of 4',5'-dihydroxy-7-methoxy-4-phenyl-5,2'-oxido-coumarin confirmed that one of the natural products isolated from Coutarea latiflora was indeed an oxido-coumarin. The third chapter examines the corrosion inhibitive properties on mild steel of naturally occurring organic compounds and their derivatives. Mono- and di-sodium salts of carboxylic acids, amino-acids, lignins, tannins and humic acids and extracts of the plants Crtisus scoparius (broom), Calluna vulgaris (heather), Pteridium aquilinum (fern), the seaweeds Fucus ceranoides and Pelvetia canaliculata and mussels Mytilus edulis all show indhibitor properties. An assessment of their relative efficiencies has also been made. The last part of this chapter discusses the corrosion inhibitive properties of oxidation products derived from castor and olive oils.

El hígado, por su especial disposición anatómica, recibe directamente la mayoría de sustancias asimiladas por el organismo, lo que hace que se encuentre expuesto a la agresión de aquellos compuestos potencialmente tóxicos. Si bien los hepatocitos disponen de sistemas metabólicos capaces de degradar y neutralizar los xenobióticos, el número de estos es extremadamente amplio. No sólo se encuentran en este capítulo fármacos como el paracetamol, la clorpromacina y otros, sino todos aquellos contaminantes que, voluntaria o involuntariamente, se ingieren con cierta asiduidad. Por todo ello, la incidencia de las afecciones hepáticas de origen tóxico es cada vez más acusada. Su etiología poco definida implica un tratamiento, en la mayoría de los casos, sintomático. El descubrimiento de la silimarina y otros principios de origen natural, ha abierto una vía de esperanza en la solución de esta casuística. Aunque es cierto que existe un grado de escepticismo con respecto a sus posibilidades cura tivas, es innegable que estos compuestos conjugan una clara acción farmacológica con una mínima toxicidad. Desde hace unos años, el Departamento de Farmacognosia y Farmacodinamia de la Facultad de Farmacia de Barcelona, investiga la actividad hepatoprotectora de compuestos polifenólicos de origen natural, en la creencia de que el estudio de las propiedades de estas sustancias permitirá el mejor conocimiento de los mecanismos biológicos implicados de la patología hepática, base de la futura instauración de una terapéutica eficaz. El hecho de que se escogiera como sujeto del presente estudio la alcachofa (Cynara scolymus L.) radica en que, a pesar de su destacada actividad colerética, no se ha demostrado de forma precisa si esta droga presenta o no propiedades hepatoprotectoras. Del mismo modo, no queda claro el papel que desempeñan los derivados polifenólicos y, específicamente, los cafeilquínicos de la alcachofa. Se ha trabajado con sustancias polifenólicas puras y con extractos de alcachofa caracterizados por técnicas de HPLC, a fin de poder relacionar las actividades detectadas con un determinado principio o grupo de ellos.

Aquesta Tesi Doctoral cobreix tres camps de la química orgànica sintètica dedicats a la síntesi de nous materials basats en hidrocarburs aromàtics policíclics (HAPs), el desenvolupament de noves metodologies sintètiques catalitzades per complexos metàl·lics, i la síntesi de derivats de productes naturals. El desenvolupament de noves estratègies per a la síntesi de nous fragments de grafè amb estructures ben definides és un camp de gran interès donada la seva potencial implementació en dispositius d’electrònica molecular. Els fragments de grafè amb estructures circulars resulten particularment interessants degut a les seves extraordinàries propietats optoelectròniques i d’autoassemblatge. En aquest context es va desenvolupar la síntesi d’un nou fragment circular de grafè d’elevada simetria C54H20, tetrabenzocircumpirè, les propietats electròniques del qual van ser examinades mitjançant microscòpia d’efecte túnel (STM). Els acens estan constituïts per anells de benzè fusionats en línia i representen un atractiu tipus de HAPs degut a les seves propietats semiconductores. Tanmateix, la seva aplicació en dispositius electrònics està limitada per la seva baixa solubilitat i la seva inherent inestabilitat. Una possible solució per salvar aquestes limitacions és preparar derivats parcialment saturats més estables, els quals poden emprar-se com precursors dels sistemes conjugats. Així doncs, va establir-se un nou mètode per a la preparació d’acens parcialment saturats basat en una ciclació catalitzada per or(I) d’1,7-enins que deriven d’un precursor comú. Aquest mètode va resultar ser general i va permetre la preparació de diversos dihidrotetracens funcionalitzats, així com d’hidroacens amb fins a nou anells linealment fusionats. L’excepcional habilitat dels complexos d’or(I) per a construir estructures policícliques complexes va ser examinada també en el marc de la síntesi de productes naturals. L’alcoxiciclació d’1,6-enins catalitzada per or(I) va permetre un ràpid assemblatge de l’esquelet tetracíclic [3,5,5,7] de les echinopines, fet què va donar lloc a un mètode per a la preparació de derivats funcionalitzats d’aquests productes naturals.
Esta Tesis Doctoral cubre tres campos de la química orgánica sintética dedicados a la síntesis de nuevos materiales basados en hidrocarburos aromáticos policíclicos (HAPs), el desarrollo de nuevas metodologías sintéticas catalizadas por complejos metálicos, y la síntesis de derivados de productos naturales. El desarrollo de nuevas estrategias para la síntesis de nuevos fragmentos de grafeno con estructuras bien definidas es un campo de gran interés dada su potencial implementación en dispositivos de electrónica molecular. Los fragmentos de grafeno con estructuras circulares resultan particularmente interesantes debido a sus extraordinarias propiedades optoelectrónicas y de autoensamblaje. En este contexto se desarrolló la síntesis un nuevo fragmento circular de grafeno de elevada simetría C54H20, tetrabenzocircumpireno, cuyas propiedades electrónicas fueron examinadas mediante microscopía de efecto túnel (STM). Los acenos están constituidos por anillos de benceno fusionados en línea, y representan otra atractiva clase de HAPs debido a sus propiedades semiconductoras. Sin embargo, su aplicación en dispositivos electrónicos está limitada por su baja solubilidad y su inherente inestabilidad. Una posible solución para salvar estas limitaciones es preparar derivados parcialmente saturados más estables, los cuales pueden usarse como precursores de los sistemas conjugados. Así, se estableció un nuevo método para la preparación de acenos parcialmente saturados, el cual está basado en una ciclación catalizada por oro(I) de 1,7-eninos que derivan de un precursor común. Este método resultó ser general y permitió la preparación de diversos dihidrotetracenos funcionalizados, así como de hidroacenos con hasta nueve anillos linealmente fusionados.
This PhD covers three fields of synthetic organic chemistry devoted to the synthesis of new materials based on polycyclic aromatic hydrocarbons (PAHs), the development of new metal-catalyzed synthetic methodology, and the synthesis of natural product derivatives. The development of new strategies for the precise synthesis of structurally well-defined novel graphene cutouts is a field of great interest due to their potential implementation in molecular electronic devices. Particularly interesting PAHs are disc-shaped fragments of graphene because of their unique optoelectronic and self-assembly properties, which are predicted to be enhanced for expanded systems. In this context, an efficient synthesis of a new discotic highly symmetric C54H20 graphene fragment – tetrabenzocircumpyrene – was developed and the electronic properties of this new graphene fragment were examined by scanning tunneling microscopy (STM). Acenes consist of planar sets of linearly fused benzene rings and represent another appealing class of PAHs due to their semiconducting properties. Nonetheless, their applicability in electronic devices is limited by their poor solubility and their inherent instability. One approach to circumvent these limitations is the preparation of more stable partially saturated derivatives, which can be used as precursors of the conjugated systems. Thus, a selective method for the preparation of partially saturated acenes under mild reaction conditions was developed based on a gold(I)-catalyzed cyclization of suitable 1,7-enynes that were assembled from a common precursor. The method proved to be general and allowed the preparation of functionalized dihydrotetracenes, as well as larger hydroacenes with up to nine linearly fused rings. The outstanding ability of gold(I) complexes to construct complex polycyclic frameworks was also examined in the context of the synthesis of natural products. Thus, the gold(I)-catalyzed alkoxycyclization of cyclopropyl-tethered 1,6-enynes allowed the ready assembly of the [3,5,5,7] tetracyclic skeleton of Echinopines, which opened an entry for the preparation of functionalized derivatives of these natural products.

El objetivo general del trabajo presentado es investigar nuevas metodologías para la síntesis de: a) nectrisina, un inhibidor de α-glucosidasas y α-mannosidasas, b) del fragmento oligosacarídico del antibiótico AT2433-A1, un antibiótico utilizado en el tratamiento de numerosos tipos de cánceres y, c) de análogos del cidofovir o HPMPC, nucleósido acíclico que incorpora una unidad de fosfonato, y que se utiliza en el tratamiento del citomegalovirus (CMV) en pacientes con SIDA. Síntesis enantioselectiva de nectrisina Retrosintéticamente la síntesis de la nectrisina puede llevarse a cabo por ciclación del aminoaldehído 2 (R4=CHO), el cual puede proceder del alqueno trans 3 mediante una reacción de dihidroxilación estereoselectiva. La síntesis de 3 puede llevarse a cabo a partir de 4 mediante elongación de la cadena utilizando la reacción de metatesis cruzada catalizada por rutenio. Finalmente, el intermedio clave 4 procede de una aminación alílica asimétrica catalizada por Pd del monepóxido de butadieno racémico 5, reacción ya descrita por Trost. La aminación alílica asimétrica del monepóxido de butadieno racémico catalizada por Pd (η3-C3H5)PdCl/DACH-naftilo transcurrió con elevado rendimiento y enantioselectividad para dar el compuesto 4. La elongación de la cadena de 4 se realizó mediante una metatesis cruzada catalizada por el catalizador de Grubbs-Hoveyda con diferentes alquenos como acroleína, 2-vinil-1,3-dioxolano, y con acrilato de etilo. Sólo en este último caso se obtuvieron resultados relevantes del compuesto 3 (R4=COOEt) como para continuar la síntesis. La reacción de dihidroxilación estereoselectiva del alqueno trans 3 (R4=COOEt) condujo al diol deseado 2 (R4=COOEt) con buena selectividad utilizando OsO4/TMEDA. La hidrólisis del benzoato con LiOH y la ciclación in situ condujo a la lactama, a partir de la cual se siguió una secuencia sintética descrita en la bibliografía, consistente en la sililación de los grupos hidroxilo, protección del grupo amino en forma de terc-butil carbamato, reducción del carbonilo y eliminación con desprotección concomitante de los grupo sililo para dar la imina, que en nuestras manos no logró llevarse a fin debido a problemas en la última etapa de eliminación para dar la imina. Síntesis enantioselectiva de análogos de Cidofovir HPMPC La síntesis de los análogos del cidofovir se planteó siguiendo un esquema sintético similar al de la nectrisina, en el que la síntesis del intermedio 7 se llevó a cabo mediante la aminación alílica asimétrica del monoepóxido del butadieno y posterior reacción de metátesis cruzada como pasos clave. En primer lugar se realizó la aminación alílica asimétrica catalizada por Pd (η3-C3H5)PdCl/DACH-naftil del monepóxido de butadieno racémico, con adenina y citosina la cual se optimizó hasta conseguir rendimientos y excesos enantioméricos superiores al 90%. Seguidamente se optimizó la reacción de metátesis cruzada de los compuestos obtenidos (6) con un alil fosfonato convenientemente protegido, obteniendo 7 con buen rendimiento. La síntesis de los análogos de cidofovir insaturados 8 y 9 se completó tras la desprotección de todos los grupos protectores con TMSBr. La síntesis del derivado saturado 10 se realizó mediante la hydrogenación (3 bares de hidrógeno, Pd/C durante 5h) y la eliminación de los grupos protectores. Síntesis enantioselectiva del fragmento oligosacarídico del antibiótico AT2433-A1 La retrosíntesis de 18 se planteó por ciclación electrófila inducida por yodo de 15, donde X debiera ser un grupo activador del doble enlace que a su vez se pudiera comportar como grupo saliente en la subsiguiente reacción de glicosilación a partir de 15. La síntesis del intermedio 15 se planteó por diferentes procedimientos y en particular a partir del sulfato 14, el cual provendría del diol 13, que a su vez provendría de la dihidroxilación de 12. El compuesto 12 debería poder obtenerse a partir de 5 por la secuencia clásica de DYKAT y metatesis cruzada. Así, a partir del compuesto 11 (R=Boc) se realizó la metatesis cruzada con diferentes alquenos y en particular con el alil fenil tioéter. Las limitaciones se encontraron en la reacción de dihidroxilación, ya que en casi todos los casos ensayados se produjo la oxidación del azufre, lo que conduciría al cambio de la selectividad en posteriores etapas como la ciclación. Se consiguió evitar la oxidación utilizando ligandos quirales en la dihidroxilación, pero con rendimientos muy bajos no compatibles con un esquema de síntesis por etapas.
The present thesis deals with the development of methodology for the syntheses of several organic molecules that were selected by their interesting biological properties: the antibiotic AT2433-A1, the glycosidase inhibidor nectrisine and analogs of the anti-viral Cidofovir (Figure 1.1) . Although apparently structurally unrelated, they were envisaged to be synthesized through common high-efficient key steps that involve metal-catalyzed process. Enantioselective Synthesis of nectrisine We explore an enantioselective synthesis of nectrisine based on Pd-catalyzed asymmetric allylic amination, cross-metathesis and dihydroxylation as key steps. Scheme 1 shows the retrosynthesis proposed, where the key synthon is the allylamine 4 which is obtained in high enantiomeric purity by a deracemization process using Pd/DACH as a catalytic system. Cross-metathesis will allow increasing the chain length, and at the same time would provide the aldehyde functionality necessary for formation of the cyclic imine moiety in the final nectrisine. Besides, configuration of double bond resulting from cross-metathesis must be E in order to provide the correct configuration of hydroxyl groups in 2 after the dihydroxylation reaction. The stereoselectivity of this reaction will be controlled by the stereocenter in the molecule, which could be also be enhanced by chiral ligands in a matched double stereodifferentiation process. The asymmetric allylic amination from racemic butadiene monoepoxide using (η3-C3H5)PdCl/DACH-naphtyl system and t-Butyl-benzoyl-imido carboxylate as a N-nucleophile proceeded with excellent yield (98%) and enantioselectivity (97%) to obtain the chiral allylic amine synthon 4. Elongation of the chain of the key chiral allylic imide with ethyl acrylate through cross metathesis using Hoveyda-Grubbs catalyst (5 mol %), proceeded quatitatively to obtain the trans alkene intermediates 3. The installation of the syn diol moiety via dihydroxylation of the alkene proceeded with high yield and good diastereoselectivity with OsO4/TMEDA. Hydrolysis of benzoate group in 2 with LiOH and in situ cyclization led to the lactam. Whose hydroxyl functionalities were fully protected by treatment with TBSCl. Subsequent protection with di-t-butyl dicarbonate (Boc) 2O and Et3N in CH2Cl2 gave desired product in 50% yield. The increased carbonyl electrophilicity resulting from NBoc protection should facilitate the smooth reduction of the lactam, which proceeded by reaction with Super Hydride® at −78°C to give lactol. Enantioselective Synthesis of Cidofovir Analogues In this context, the retrosynthetic proposal is shown in Scheme 2. Cidofovir (HPMPC) analogues could be obtained by double bond reduction of product 7 followed by protecting group cleavage on compound 11. Compound 7 in turn can be synthesized from compound 6 via chain elongation mediated by cross-metathesis reaction. Lastly, chiral synthon 6 could be obtained by a palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) from racemic butadiene monoepoxide (5). The asymmetric allylic amination of racemic butadiene monoepoxide with cytosine as N-nucleophile was carried out with (η3-C3H5)PdCl/DACH-naphtyl system to obtain chiral allylic cytosine in 85% yield and 72% ee. The reaction was successfully expanded to other pyrimidine and purine bases, among which adenine afforded chiral allyl adenine in 90% yield and 92% ee. Chain elongation via Ru-cross metathesis of key allylic nucleobases and diethyl allylphosphonate with second generation Grubbs catalyst (5 mol%), produced desired compounds in 92% and 90% yield, respectively. Deprotection of all protecting groups with TMSBr afforded the desired unsaturated acyclic nucleosides 8 and 9 in good yields. Hydrogenation with (H2, /Pd/C) at 3 bar rendered the saturated Cidifovir analogues 10. Approaches to the Enantioselective Synthesis of AT2433-A1 The objective of this work was to explore a new enantioselective method to obtain AT2433-A1 with special focus on the synthesis of the 2, 4-dideoxy-4-amino-xyloside moiety. The retrosynthetic proposal is shown in Scheme 5.6. The aminodeoxysugar (19) could be obtained from 16 by eletrophile-induced cyclization. A key point is the selection of group X, since it must control the regioselectivity of the cyclization to an endo-mode and eventually must behave as a leaving group in a future glycosylation reaction. Amino alcohol 16 could be prepared from allylic amine 13 by dihydroxylation, sulphate formation and elimination. Compound 13 can be synthesized from allyl amine 12 via chain elongation mediated by cross-metathesis reaction. Lastly, chiral allyl amine 12 could be obtained, similarly to the previous chapters, by a palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) from the racemic butadiene monoepoxide 5. On the other hand, the intermediate 15 could be also obtained by addition to the Garner aldehyde (18) followed by deprotection of the protecting groups in 17. The asymmetric allylic amination from racemic butadiene monoepoxide using (η3-C3H5)PdCl/DACH-naphtyl system and imide as a nitrogen nucleophile proceeded with good yield (96%) and enantioselectivity (90%). Chain elongation of key chiral allylic amine 12 was carried out by cross metathesis with allyl phenyl sulphide with Hoveyda-Grubbs catalyst (5 mol%) to obtain the corresponding trans alkene 13 in 80% yield. The installation of the diol moiety with OsO4 was unsuccesful, due to the competitive oxidation of sulfur, preventing the completion of the synthesis.

Crude extracts of the rare macrofungus Serpula sp. collected from a wooded area in Sri Lanka showed antimicrobial activity. The novel fungal metabolite serpulanine (2.1) was isolated from the crude extract in very small amounts along with a number of additional secondary metabolites. In order to obtain sufficient quantities of serpulanine (2.1) for biological evaluation, a synthetic route was developed to the natural product and a small library of analogs that have been evaluated in a panel of bioassays. Serpulanine (2.1) inhibits the histone deacetylase I/II with a clear dose response curve. Halitoxins (3.1) that are frequently isolated from marine sponges have a complex macrocyclic chemical structure made of different numbers of monomeric alkylpyridinium units. An unknown halitoxin-related natural product named alotau potently inhibited the dephosphorylation activity of calcineurin. With the goal to elucidate the structure of alotau, compounds of one, two and three pyridinium rings (3.10, 3.7 and 3.8) were synthesized. Though these compounds have NMR spectra similar to the natural alotau, according to bioassay results, none of them recapitulates the activity of the unknown natural product alotau. (+)-Makassaric acid 4.1 was isolated in the Andersen Lab from the marine sponge Acanthodendrilla sp. It showed promising activity in a zebrafish screen for new drugs to treat stroke patients. The convergent synthetic scheme shown below was undertaken to conduct structure activity relationship (SAR) studies. The key intermediate 4.17 has been obtained, and further synthetic efforts will be needed to produce 4.1.
Science, Faculty of
Chemistry, Department of
Graduate

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.

Bioassay guided fractionation of a crude extract of the marine sponge Neopetrosia exigua resulted in the first reported isolation of exiguamines A and B. These pyrroloquinone alkaloids have an unprecedented hexacyclic skeleton that has not been previously encountered in natural products. Biological studies have identified exiguamine A as a potent in vitro inhibitor of the enzyme indoleamine-2,3-dioxygenase (IDO). IDO is an enzyme expressed by tumor cells to evade the immune system. Inhibitors against this enzyme may allow the immune system to attack cancer cells, making this enzyme a potential drug target for anti-cancer agents. Investigation of the crude extract of a Bacillus sp. collected in Dominica led to the isolation of the known diketopiperazine cyclo(S-Val-S-Phe) (3.9). In vitro biological studies revealed that cyclo(S-Val-S-Phe) is able to promote neurite outgrowth, even in the presence of physiological inhibitors. In vivo studies have shown that cyclo(S-VaI-S-Phe) is able promote sprouting in serotonergic and adrenergic axons. Synthesis of the other three diastereomers led to the discovery that cyclo(R-Val-R-Phe) is also an in vitro activator of axonal outgrowth. Inhibitors of the G2 checkpoint are able to increase the cytotoxicity of DNA damaging chemotherapeutics. Bioassay guided fractionation of an extract of the South American plant Duguetia odorata led to the isolation of the G2 checkpoint abrogator, oliveroline. This investigation also led to the isolation of the previously unreported alkaloid N-methylguatterine, and the known alkaloids dehydrodiscretine and pseudopalmatine. Chemical investigation of the marine sponge Myrmekioderma granulatum led to the isolation of the new compounds abolenone and myrmekioside C, as well as the known compounds curcudiol, curcuphenol, abolene and sesquiterpenoid. Biological studies of these compounds revealed that curcudiol is a ligand of the sex hormone-binding globulin. This protein is involved in transporting and regulating the concentration of steroids such as testosterone and estradiol. Many pathological conditions have a lower plasma concentration of these steroids. Ligands to SHBG can release steroids into the blood, so this protein is a potential drug target to treat conditions where a hormone insufficiency is present.

Two new β-carboline alkaloids were isolated from the bryozoan Cribricellina cribraria. One of these, 1-vinyl-8-hydroxy-β-carboline, was the major cytotoxic component of the extract, while the other had a novel sulphone structure. Several other known β-carboline alkaloids were also isolated from the extract. To investigate structure-activity relationships in these compounds, several derivatives of the major alkaloid were prepared and a number of 1-substituted β-carboline alkaloids synthesised. Nmr spectroscopic studies of these compounds were carried out and previously published ¹³C nmr data for some of these compounds revised. Homarine was isolated as the major water soluble component of the extract and the sterol composition examined. Known β-carboline alkaloids were isolated from the related bryozoan Margaretta barbata. The known biologically active compounds, girolline and hymenialdisine were isolated from the sponge Axinella sp. 2. As some discrepancies between the experimental and published data on hymenialdisine were noted, an X-ray crystal structure analysis was performed. Oroidin, homarine and taurine were also isolated from the extract and the sterol composition found to consist exclusively of ring-contracted A norstanols. An extract of the sponge Stylopus australis was found to contain a new sterol sulphate and two derivatives of this compound were prepared. The full assignment of the ¹H nmr spectrum of the sulphate was achieved with the aid of COSY, nOe, HETCOR and XCORFE nmr experiments. The glyceryl ether, chimyl alcohol was also isolated from the sponge. An extract of the related sponge, Hymedesmia sp. 1 was examined and rhodoic acid isolated as the major water soluble component, along with homarine. The sterol compositions of Stylopus australis and Hymedesmia species 1 and 2 were examined for comparative purposes. Studies on an extract of the sponge Hymeniacidon hauraki led to the isolation of a new furan fatty acid. The sterol corbisterol and its peroxide were isolated from one sample of the sponge and this led to an examination of infraspecific sterol variation in this species. A screening procedure of biologically active natural product extracts has been developed. The procedure involves examining the chromatographic behaviour of the biological activity of an extract and is designed to detect known biologically active compounds and to determine the best means of handling extracts containing unknown biologically active components.

An investigation of the marine sponge Halisarca sp. was carried out following the discovery of strong activities in antiviral and P388 murine leukaemia assays of an extract from this sponge. A polyether type of compound is suspected as the cause of this activity. The investigation of Halisarca sp. made a significant contribution to the development of a chemical screening process. The absolute configuration of pateamine has been elucidated by a combination of degradative and synthetic chemistry utilising formation of diastereoisomers with Mosher's acid. Several other derivatives of pateamine are reported. The algal metabolite thyrsiferol has been isolated from the digestive gland of the marine mollusc Aplysia parvula. The egg masses of A. parvula have also been examined. The NMR characterisation of the thyrsiferol has been extended through the extensive use of one- and two- dimensional spectroscopic experiments.

The halichondrins are a series of polyether macrolides displaying potent in vitro and in vivo antitumour activities and, as such, represent important leads as anticancer drugs. These compounds had previously been isolated from a number of unrelated marine sponges, such as Lissodendoryx sp., a high yielding deep-water sponge located off the Kaikoura coast of New Zealand. Structure-activity relationships in the halichondrin senes have now been investigated. Hemi-synthetic modifications of selected naturally-occurring halichondrins have produced over fourteen new analogues. The biological activities of twelve of these analogues have been assessed in an in-house P388 in vitro assay and in the National Cancer Institute's (USA) in vitro sixty cell-line human tumour panel. An analysis of these data has shown that the lactone ring (C1-C30), the olefinic functionalities (C19 and C26), the natural C38 stereochemistry and the tricyclo ring system (C-E rings) are essential structural features of the halichondrins. The characterisation of the hemi-synthetic derivatives has been facilitated by the full NMR spectroscopic assignments of halichondrin B and homohalichondrin B. The future progress of the halichondrins as anticancer drugs will have been assisted by the development of an understanding of the general chemistry of the halichondrins.

The bioactivity directed analysis of the extract from a sponge of the genus Sarcotragus led to the isolation of a series of bioactive sesterterpenes, of which variabilin (1a) was the major component. The sesterterpenes (29a), (30) and (31a), along with the related C₂₁ furanoterpene (32), were present in lesser amounts. The unequivocal assignment of the stereochemistry of the 20,21 double bond in variabilin as 20(Z) was achieved through examination of the22-O-methyl derivative (1b) of variabilin and the isolation of the variabilin isomer (29a) with the 20(E) stereochemistry. Variabilin was also isolated from a sponge of the genus lrcinia. The four related bioactive sesterterpenes (33b), (34b), (35b), and (36b) together with (31b) were isolated from a methylated extract from the same sponge. Variabilin autooxidised in the presence of light and air to form a mixture of products that underwent further oxidation on standing. The 22-O-methyl derivative (1b) of variabilin did not autooxidize but underwent oxidation in the presence of the singlet oxygen sensitizer, rose bengal. The products from this oxidation reaction were (48b), (49b), (50b), (51b), (52b), (53b), (50b), (61b), (62b), (63b), (64b) and (65b) and these were the same as the products from the variabilin autooxidation with the exception of the methyl group at C₂₂. Variabilin autooxidation was shown to occur through the production of singlet oxygen and subsequent oxygen addition to the furan moiety. The production of singlet oxygen occurred through a sensitization mechanism involving the variabilin tetronic acid moiety. To investigate structure-bioactivity relationships in variabilin and related sesterterpenes, derivatization of the furan and tetronic acid moieties in variabilin was carried out. 22-O-Me variabilin (1b), in contrast to variabilin, reacted favourably under most furan reaction conditions and so a number of reactions were carried out on (1b) also. Hydrogenation of variabilin gave the cytotoxic compound (73). Dials-Alder addition of DMAD to variabilin gave the cytotoxic compounds (74a) and (75a) and acylation gave the cytotoxic compounds (81) and (82). Reduction of these acylation products gave the cytotoxic derivatives (83) and (84). The non-cytotoxic compound (85) was formed on reaction of p-bromobenzoylchloride with variabilin. Dials-Alder addition of DMAD to 22-O-Me variabilin gave the cytotoxic compounds (74b) and (75b) and addition of 4-phenyl-1,2,4-triazoline-3,5-dione (phenyl-TD) (78) gave the potential antiviral compounds (76) and (77). A cytotoxic sesquiterpene (86) with a tricyclo[6.3.1.0.²,⁵]dodecane skeleton has been isolated from the extract of a New Zealand Eurypon sp. of sponge. Two derivatives, (87) and (88), of this sesquiterpene have also been isolated, probably as artefacts arising during the isolation procedure. The structure of a spirosesquiterpene (89), also obtained from the sponge extract, has been determined. Previously published nmr assignments for β-caryophyllene alcohol (90) have been revised. Three further compounds, labeled unknowns a-c, were isolated, but their structures were not determined. One of these unknowns (unknown a) was probably a sesquiterpene, and was shown to be cytotoxic, while the remaining two (unknowns band c) gave spectroscopic data which indicated that while they were very closely related to one another, they were not sesquiterpenes. Bioassay directed isolations of the active components from a new sponge, genus Chondropsis, and the bryozoan, Margaretta barbata, were attempted. The bryozoan, Margaretta barbata had previously been shown to exhibit significant in vivo P388 activity. For the Chondropsis species the components responsible for the observed biological activity appeared to be very minor components of the overall sponge and isolation of the active compounds was not achieved. For the bryozoan the more polar active material was present in reasonable abundance and a compound (unknown d) giving in vitro P388 activity was isolated. However full characterisation of this compound was not achieved. The compound, or compounds, responsible for the biological activity shown by the less polar material were not isolated. Sterols were shown to be major components of the non-polar organic material in both the sponge and bryozoan species studied. For the Chondropsis sponge the major sterol component was identified as 24-methylene-cholesterol (92). For the bryozoan, Margaretta barbata, the major sterol was identified as cholesterol (93) with 24-methylene-cholesterol (92) and cholest-4-en-3-one (94) also being identified. The major organic water soluble compound was identified as homarine (95).

The first chapter of this thesis deals with the synthesis, cyclisation of 2-aminobenzophenones and biomimetic synthesis of acridone alkaloids. The biogenesis of acridone alkaloids produced in tissue culture is described. 2,4,6-Triacetoxy-2'-methylaminobenzophenone was prepared to study its cyclisation to the acridone ring system. 2,4,6-Triacetoxy-2'-methylaminobenzophenone was converted to 1,3-dihydroxy-N-methylacridone. The intermediate 2,4,6-trihydroxy-2'-methylaminobenzophenone was also synthesised and found to be highly reactive, cyclising extremely easily to the acridone thus confirming the probable role of the 2'-aminobenzophenone as a precursor in the biosynthesis of acridone alkaloids in tissue cultures. The second part is concerned with a phytochemical investigation of two species of Ruta namely Ruta montana and Ruta chalepensis from Turkey. This chapter deals with the isolation and identification of coumarins and alkaloids from both species of Ruta. The compounds which are isolated and identified from root extracts of Ruta montana are chalepensin, rutamarin, xanthotoxin and marmesin. From the root extract of Ruta chalepensis the alkaloid skimmianine was isolated together with chalepensin, rutamarin, and bargapten. An as yet, unidentified sugar was isolated. The structures of these natural products were elucidated on the basis of spectroscopic data together with comparisons with published data and authentic samples (wherever possible).

This thesis consists of three relative independent projects all of which concentrate on the syntheses of biologically active natural products. In the first project, a convenience route for synthesis of [8-³H]-berberine sulfate has been established and two routes for preparation of ¹⁴C labelled berberine are explored. A series of compounds containing a methylenedioxyphenyl functionality have been synthesised for using as antigens in immunological studies. The second project concerns development of chemistry directed towards the stereocontrolled synthesis of Baogongteng A, a novel 2,6-disubstituted tropane alkaloid which is a powerful M-cholinergic agonist used in the treatment of glaucoma. By exploiting 4-hydroxy-L-proline as the chiral synthon, useful methods such as preparation of 2-formyl 4-hydroxy-L-proline derivatives, and the stereoselective bromination of the C-3 of 4-hydroxy-L-proline derivatives, have been established. About forty new organic compounds have been synthesised and identified. The final project concerns exploration of new routes for the syntheses of biotin biosynthetic precursors and their fluorined analogues which are types of compounds potentially valuable in agricultural chemistry. This work has led to the development of methods of wide application, such as the preparation of highly purified N-Boc-L-alaninal, which should prove to be of use in future studies in this and related fields.

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.

A convergent approach was applied to the synthesis of a range of Xanthomonas pigments and a number of selected analogues, with a view to understanding more about their photoprotective properties, and utilising the group’s iterative Heck-Mizoroki/ iododeboronation cross-coupling methodology to access polyenyl intermediates. This involved the synthesis of a number of key arenyl building blocks. Three polyenyl building blocks were accessed via sequential Heck-Mizoroki and iododeboronation reactions, providing flexibility in the construction of the pigments and their analogues. Following some optimisation of final cross-coupling reactions, two truncated bacterial pigment analogues were successfully synthesised, with evidence of the synthesis of one of the natural product pigments also obtained. The key challenges in these syntheses lay in the considerable instability of many of the polyenyl intermediates (particularly the polyenyl iodides) and in the successful coupling onto the arenyl intermediates. Extensive NMR analysis, along with UV-Vis analysis provided insight into the photochemical behaviour of the truncated model compounds, and also corroborated the initial characterisation obtained by Andrewes et al. when they isolated xanthomonadin in 1976. Studies were also undertaken into novel methods of polyene synthesis, with vinyl iodide established as a potential Heck-Mizoroki coupling partner, providing access to a key dienyl boronate building block. This dienyl boronate was used to access a range of terminal dienes and trienes, providing a versatile route to such compounds. The group’s Heck-Mizoroki cross-coupling conditions were also re-optimised to operate at room temperature, at low catalyst loadings, and on much shorter timescales than had been utilised previously.

Throughout this work, this study tries to understand “how organic cosmetics companies advertise through magazines?”

In the first place, the theories about green marketing will be studied and the focus will more specifically be on green marketing communication and the communication on general.

Then, we will analyze qualitatively and quantitatively the organic cosmetics’ communication in fashion and health magazines. We will try to compare the differences in communication between these two magazines’ types.

Afterwards, we link the analysis of advertising with the theory in order to underline if the organic cosmetic companies apply the theory in their communication strategy.

To conclude, we will try to answer the question: “how organic cosmetics companies advertise through magazines?”

Polyketide secondary metabolites constitute a structurally-diverse and clinically-important family of natural products. The wide range of biological activities represented by these substrates have contributed to therapeutic agents with annual sales exceeding $20B USD. Large multi-domain proteins called polyketide synthases (PKSs) use simple building blocks to generate highly-oxygenated and stereochemically-rich frameworks with astonishing selectivity. These substrates often feature rigidifying biases imposed by macrocyclic lactones and substituted heterocycles, which can impact their bioactive conformation. The work of this dissertation combines synthetic chemistry and biochemistry to investigate chemoenzymatic production of macrocyclic polyketide natural products. Research focused on validating a transannular oxa-conjugate addition strategy to assembly 2,6-cis-tetrahydropyran (THP) ring systems, as demonstrated by synthesis of the macrocyclic core to neopeltolide. Ultimately, we wish to apply this chemistry to de novo PKS pathways for rapid, reliable, and sustainable production of THP-bearing products like neopeltolide, and toward building SAR libraries. Additionally, a second study probed the specificity of the macrolactonizing thioesterase (TE) domain from the 6-deoxyerythronolide B (DEBS) biosynthetic pathway. This pathway is the paradigm for type-I PKS systems, and is responsible for producing the macrolide core of erythromycin. Our on-going research evaluates the limits of promiscuity within this specific catalytic domain, to characterize the structural elements required to accurately predict macrolactonization. The long-term goal of this study is to assess the potential applicability of DEBS TE as a generalized cyclization biocatalyst for combinatorial biochemistry and chemoenzymatic research.

Les polyphénols naturels forment des complexes non-covalents dans lesquels le π-stacking et les liaisons hydrogène jouent un rôle clé dans la stabilisation. Les calculs DFT incluant la dispersion (DFT-D), la description des processus d'agrégation non-covalente de produits naturels devient fiable. Dans ce travail, les méthodes DFT-D sont appliquées à i) la compréhension de la biosynthèse stéréo- et régio-sélective des oligostilbenoïdes, ii) la prédiction de l'agrégation des antioxydants naturels au sein de la membrane bicouche lipidique, qui pourrait rationaliser la synergie de la vitamine E, la vitamine C et polyphénols dans leur action antioxydante, et iii) la modulation des propriétés optiques de dérivés de chalcones
Natural polyphenols form non-covalent complexes in which π-stacking and H-bonding play a key stabilizing role. The dispersion-corrected DFT calculations have paved the way towards reliable description of aggregation processes of natural products. In this work, these methods are applied at i) understanding of stereo- and regio-selective oligostilbenoids biosynthesis; ii) predicting natural antioxidant aggregation within lipid bilayer membrane, which may allow rationalizing the synergism of vitamin E, vitamin C and polyphenols in their antioxidant action; and iii) modulating optical properties of chalcone derivatives

Two terrestrial organisms were explored for biologically active and/or novel components. The genus Paeonia has long been know to contain numerous components that display a vast array of biological activities. The extract of P. lutea showed significant antiviral activity. Using bioassay-guided separation techniques three previously known compounds, paeonol (11), paeoniflorigenone (10) and methyl gallate (16), were identified using mass spectrometry and NMR techniques. These components showed varying biological activities and constituted the majority of the bioactivity in P. lutea. The chemistry of the New Zealand fungus Favolaschia calocera had not previously been investigated. A crude extract showed significant cytotoxicity against the P388 cell line and through bioassay-directed chromatography, 9-methoxystrobilurin L (33) was isolated as a novel cytotoxic compound. The structure was determined by MS and NMR techniques including HMBC, HMQC, COSY and nOe enhancements. Two closely related novel compounds were also characterised from the F. calocera extract. These were methyl-4,6-(E,E)-3-benzoyl-7-phenylheptadienoate (35) and the corresponding free carboxylic acid (36). Neither were found to have significant biological activity in the assays screened. A mixture of triglycerides (34) was also isolated and was analysed using NMR techniques followed by transesterification and GCMS analysis of the corresponding methyl esters.

The roots of a species of New Zealand native flax, Phonnium tenax and a commercial herbal preparation of the root were examined for novel or biologically active compounds. The species Phormium tenax has been examined chemically in the past and has yielded a number of novel and biologically active compounds. Missing from this body of work was an investigation into an aqueous extract of the roots of the plant. The commercial herbal preparation, "Fluid of Flax, Manaaki Huia" was such an extract and from this three novel aromatic glycosides were isolated. The herbal preparation was found to contain one biologically active compound, 1- 0-[β- glucopyranosyl-(16)-O-β-xylopyranosyl]-4-hydroxymusizin. The structure was identified by mass spectrometry and NMR techniques which included HMBC, HSQC, ID TOCSY and nOe enhancements. Two related glycosides, 1- 0-[β- glucopyranosyl-(16)-O-6-deoxy-β-mannopyranosyl]-4-hydroxymusizin and 1- 0-[β- glucopyranosyl-(16)-O-6-deoxy-β-mannopyranosyl]-musizin were isolated from a methanol extract directly from the roots of Phormium tenax. Both of these compounds were present as minor components in the herbal preparation. Neither of these glycosides showed any significant bioactivity in the in-house bioassays available.

Natural products are a potent reservoir of bioactive compounds, but their exploration is often hampered by the limited quantities available from natural sources. Total synthesis of natural products alleviates this restraint, and necessitates development of new chemistry to grant access to complex structures. In this thesis, we develop synthetic routes toward two quinoid natural products. Taiwaniaquinone G is a representative trans-configured taiwaniaquinoid, synthetically underrepresented compared to cis-configured taiwaniaquinoids, isolated from the bark of the endangered tree Taiwania cryptomeriodes. We developed a polyene cyclisation strategy which would form the tricyclic core in a single step from a linear precursor, but it proceeded cis-selectively instead of the expected trans-selectivity. DFT calculations were performed, and the cis-configured intermediate was found to be stabilised hyperconjugatively. Several strategies were explored to overcome this stereochemical preference, but ultimately the synthesis was continued towards the cis-configured 5-epi-taiwaniaquinone G, which was synthesised in 8 steps and 4.2% overall yield, the shortest synthesis to date. Elisabethin A is a minor metabolite isolated from the Caribbean sea whip Pseudopterogorgia elisabethae, and several groups have attempted its synthesis due to its unique ring structure. We review evidence that a reported total synthesis was unsuccessful, and provide computational support for the Diels-Alder product proposals of Zanoni et al. We explore a route to elisabethin A which would circumvent problems experienced in the terminal epimerisation step by Rawal et al. using a radical leaving group to invert the stereochemistry at the required tertiary carbon centre. A synthesis of the aryl core and pendant tail fragments was completed. Several strategies are explored to unite the precursor fragments. Model systems are investigated for our proposed Claisen rearrangement and radical inversion strategies.

Although global cases and death from malaria have reduced over the last ten years, malaria is still a significant infectious disease. This disease kills about 2000 people per day. There is currently no licenced vaccine and current drugs are failing due to parasite drug resistance. Thus, there is an urgent need to develop new drugs to prevent and treat this disease. Natural products and their derivatives have played a significant role in drug discovery, since they have been an important source or inspiration for numerous current drugs. Australian macrofungi have rarely been studied for their potential as sources of new bioactive natural products, and in the antimalarial drug discovery realm, this is a pioneering study. As part of a research program aimed at identifying new antimalarial lead compounds or drugs from nature, a pre-fractionated fungal library was screened for antimalarial activity. All macrofungi used during these studies were collected from a variety of ecosystems found within the state of Queensland, Australia. A taxonomically diverse set of fungi were used with 37 families and 62 genera represented. The library consisted of 2,035 fractions obtained from C18 HPLC fractionation of 407 DCM/MeOH fungal extracts, with five fractions collected for each extract. A radiometric growth inhibition assay was used to screen the fractions against the chloroquine sensitive Plasmodium falciparum 3D7 malaria parasite line. Of the 2,035 fractions screened, 20 displayed inhibition of >80% towards P. falciparum, the cut off selected for pursuing lead fractions. Bioassay- or UV-guided fractionations were performed on three fungal samples, and several antimalarial natural product compounds were purified and their chemical structures determined using a combination of 1D/2D NMR, MS, and UV data.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Science, Environment, Engineering and Technology
Full Text

Investigations into radical and palladium(0) cyclisations onto the C-2 position of the 3H-quinazolin-4-one moiety have been made. This has led to the syntheses of a number of biologically active quinazolinone natural products using alkyl, heteroaryl and acyl radical cyclisations. The reactions proceeded via a homolytic aromatic substitution mechanism. As such, fully rearomatised products were recovered. A C-2 radical 3H-quinazolin-4-one building block was also prepared. This turned out to have only limited synthetic applications. Radical cyclisations onto aryl groups were carried out using this building block.