This thesis comprises both a natural product investigation and a synthetic component. The natural product investigations are presented in Chapters Two and Three. In Chapter Two the isolation and spectroscopic identification of the new isocopalane diterpene 12S,13R,14Sisocopalan- 13-ol-12,14-diacetate (2.1) and two known 3-(14S)-isocopal-12-ene-15-oyl-1- acetyl-sn-glycerol (2.2) and 3-(14S)-isocopal-12-ene-15-oyl-2-acetyl-sn-glycerol (2.3) from a single, large, unidentified sub-Antarctic nudibranch, collected near Marion Island, approximately 2000 km south of Cape Town are described. Chapter Three discusses the isolation, spectroscopic structure elucidation and anti-oesophageal cancer activity (3.1-3.4 only) of two known labdane diterpenes 6β,7α-diacetoxylabda-8,13E-dien-15-ol (3.1) and 2α,6β,7α-triacetoxylabda-8,13E-dien-15-ol (3.2) and one new 6β,7α,15-triacetoxylabda 8,13E-diene (3.3), as well as new 3α,11-dihydroxy-9,11-seco-cholest-4,7-dien-6,9-dione (3.4) and cholest 7-en-3,5,7-triol (3.5) from the endemic pulmonate mollusc, Trimusculus costatus. The absolute configuration of 3.2, and hence 3.1 and 3.3 (from biogenetic arguments) was determined through X-ray diffraction of a single crystal of the camphanate ester of 3.2. The absolute configuration of the secondary hydroxyl at C-3 of 3.4 was established using the Modified Mosher’s method. The synthetic component of the thesis commences in Chapter Four with the semi-synthesis of labdane diterpene nitriles 9α-cyano-15,16-epoxy-7β-hydroxylabda-13(16),14-dien-6-one (4.1), 9α-cyano-15,16-epoxy-7-hydroxylabda-7,13(16),14-trien-6-one (4.2) and 9α-cyano-15,16- epoxy-6β,7β dihydroxylabda-13(16),14-diene (4.3) from the terrestrial labdane diterpene, hispanolone (4.4). This work is an extension of previous synthetic studies directed towards the synthesis of T. costatus metabolites. Diterpenes 4.1-4.3 exhibited in planta activity against the economically important crop pathogens, Magnaporthea grisea and Puccinia recondita. Chapter Five describes the successful semi-synthesis of two isomeric marine molluscan labdane diterpene aldehyde metabolites, labd-13E-ene-8β-ol-15-al (5.1) and labd-13Z-ene- 8β-ol-15-al (5.2) from the commercially available, terrestrial plant derived, labdane diterpene manool (5.3). Diterpenes 5.1 and 5.2, originally isolated from the Mediterranean nudibranch,Pleurobranchaea meckelii and selected diterpenes arising from this synthesis were evaluated for their activity against an oesophageal cancer cell line (WHCO1). Chapter Six further develops the research discussed in Chapter Five, where ethyl 17-norabiet-13(15)-E-en-8β-ol- 16-oate (5.49) and ethyl 17-norabiet-13(15)-Z-en-8β-ol-16-oate (5.50) were first semisynthesized serendipitously. Based on their structural relationship to naturally occurring tricyclic diterpenes with anti-plasmodial activity, tricyclic diterpenes, 17-norpimaran-13α- ethoxy-8,16-olactone (6.6), 17-norisopimar-15-ene-8β,13β-diol (6.7), 17-norisopimarane- 8β,16-diol (6.8) and 17-norabiet-13(15)-ene-8β,16-diol (6.9) were semi-synthesized from the terrestrial labdane diterpene, 5.3, and critically evaluated for their antimalarial potential from parasite inhibition and haemolytic studies.

This thesis is divided into two parts. The first part (Chapter Two) documents a bioassay guided investigation of the ethyl acetate extracts of four marine invertebrates from Mozambique (an Irciniid sponge, a Haliclona sp. sponge, an ascidian tentatively identified as Diplosoma sp., and the soft coral Cladiella kashmani). Eight known compounds [ilimaquinone (2.1), renierone (2.7), N-formyl-1,2-dihydrorenierone (2.8), 1,6-dimethyl-7-methoxy-5,8-dihydroisoquinoline-5,8-dione (2.9), mimosamycin (2.10) 7Z-allylidene-5-hydroxy-7,7a-dihydro-2H-cyclopenta[b]pyran-6-one (2.11), flaccidoxide (2.18) and 11S,12S-epoxycembra-1Z,3E,7E-trien-14S-ol (2.19)] and a new diterpene [13S,14R-diacetoxy-11S,12R-epoxycembra-1Z,3E,7E-triene (2.20)] were isolated and identified using standard spectroscopic techniques. Anomalies in the published spectral data of 2.1 and 2.8 were exposed and corrected, and the absolute stereochemistry of the cembrane diterpenes 2.18 and 2.20 established using the modified Mosher’s method. The comparative activities of the nine natural products against four cancer cell lines (A549, LOX, OVCAR3, SNB19) are reported. The second part of the thesis (Chapter Three – Chapter Six) is concerned with an ecological, structural and synthetic study of diterpenes from the endemic South African pulmonate limpet Trimusculus costatus. Two new labdane diterpenes [6b,7a-diacetoxylabda-8,13E-dien-15-ol (3.10) and 2a,6b,7a-triacetoxylabda-8,13E-dien-15-ol (3.11)] were isolated from T. costatus and evaluated for anti-feeding activity against the common predatory fish Pomadasys commersonnii. A strategy for the semi-synthesis of 3.10 from rhinocerotinoic acid (4.14), a diterpene reportedly present in the ubiquitous South African shrub Elytropappus rhinocerotis, was devised in order to allow further bioactivity tests to be performed and unequivocally assign the unknown absolute stereochemistry of the T. costatus metabolites. Attempts to isolate rhinocerotinoic acid from local specimens of Elytropappus rhinocerotis were unsuccessful, and as the repetition of a published synthesis of 4.14 from (-)-sclareol (4.15) gave rhinocerotinoic acid in unacceptably low yields with poor stereoselectivity, an improved synthesis of 4.14 is presented. Comprehensive studies using hispanone (5.1) as a model compound showed that 6,7-dioxygenated labda-8-enes could be prepared from compounds possessing a 7-oxo-labda-8-ene skeleton with some degree of stereocontrol. In the process, fourteen new hispanone analogues were prepared and most of these were tested for activity in a suite of ten agro-chemical assays. The novel compound 7b-hydroxy-9a-carbonitrile-15,16-epoxylabda-13(16),14-dien-6-one (5.34) exhibited significant activity against the crop fungus Phytophthora infestans and is currently being subjected to further agro-chemical tests. Unfortunately, the results from the oxygenation study performed on the model compound 5.1 could not be directly extrapolated to rhinocerotinoic acid. Attempts to prepare the naturally occurring 3.10 from 4.14 via an alternative route were unsuccessful but yielded an analogue of 3.10 in which the substituents at C-6 and C-7 are in a diequatorial rather than a diaxial configuration.

This thesis is divided into two parts and the rationale of the research conducted is based on the cytotoxicity of the prenylated quinones 1.24-1.29, isolated from the South African nudibranch Leminda millecra, against oesophageal cancer cells. The first part (Chapters 2 and 3) of the thesis initially documents the distribution of cytotoxic and antioxidant prenylated quinones and hydroquinones in the marine environment. We have been able to show, for the first time, that these compounds can be divided into eight structural classes closely related to their phyletic distribution. Secondly, we attempted to synthesize the two marine natural products 1.24 and 1.26 in an effort to contribute to an ongoing collaborative search with the Division of Medical Biochemistry at the University of Cape Town for new compounds with anti-oesophageal cancer activity. Accordingly, we followed the published synthetic procedure for 1.26 and, although we were unable to reproduce the reported results, we have generated five new prenylated quinone analogues 3.53-3.55, 3.63 and 3.71, which are a potentially viable addition to our ongoing structure-activity relationship (SAR) studies. Moreover, we embarked on a 7Li NMR mechanistic study for the synthesis of 3.2 from 3.1 which rewarded us with an improved and reproducible methodology for this crucial reaction that is detailed in Chapter 3. The second part of this thesis (Chapters 4 and 5) is concerned with a synthetic, structural, electrochemical and biological exploration of the 1,4-naphthoquinone nucleus as a primary pharmacophore in our search for new chemical entities which can induce apoptosis in oesophageal cancer cells, thus contributing to our overall ongoing SAR study in this class of compounds. Seven new naphthoquinone derivatves (4.19, 4.30, 4.31, 4.33 and 4.46-4.48) of the natural products 2-deoxylapachol (2.44), lapachol (4.1) and β-lapachone (5.2) were synthesized and 2-(1`-hydroxy-`-phenylmethyl)-1,4-naphthoquinone (4.29) was found to be the most cytotoxic (IC50 1.5 μM) against the oesophageal cancer cell line WHCO1, while 5.2, which is currently in phase II clinical trials as an anticancer drug, was found to be similarly active (IC50 1.6 μM). Electrochemical investigations of the redox properties of the benzylic alcohol derivatives 4.29-4.31 indicated a higher reduction potential compared to their oxidized counterparts 4.45-4.48, and this finding has been correlated to the increased activity of 4.29-4.31 against the WHCO1 cell line. Additionally, 4.29 is synthetically more accessible than either 1.26 or 5.2 and potentially a lead compound in our search for new and more effective chemotherapeutic agents against oesophageal cancer

No description available.

Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

The increasing emergence of multi-drug-resistant microorganisms has led the World Health Organisation to plead for action to be taken against antimicrobial resistance. The fungal secondary metabolite (+)-pleuromutilin displays antibacterial activity with a novel mode of action: pleuromutilin derivatives bind to functionally important nucleotides within the peptidyl transfer centre of the prokaryotic ribosome and inhibit bacterial protein synthesis. The first non-racemic total synthesis of the antibiotic natural product pleuromutilin has been developed. A chiral pool strategy has been employed to gain access to the cyclisation substrate, which underwent a SmI2-mediated cyclisation cascade to give the 5,6,8 tricyclic core in a single step. The reaction proceeded with excellent diastereocontrol at the four contiguous stereocentres generated during the cascade. Elaboration of the cyclisation product to (+)-pleuromutilin was achieved by electron transfer reduction of the hindered ester at C5, stereoselective introduction of the hydroxyl at C11 and installation of the quaternary stereocentre at C12. Finally the first efficient conversion of (+)-mutilin to the target was developed. This strategy is now being used for the synthesis of simplified novel analogues of pleuromutilin: access to a range of simplified cores has been demonstrated in 5 steps.

Magister Scientiae - MSc / Early man dabbled with the use of plant extracts to cure ailments. This practice has been passed down from generation to generation and today more than 50% of the world'sdrugs are natural products or derivatives thereof. Scientists have thus established a branch of research called natural product research. This branch of research involves the identification and purification of secondary metabolites with a specific biological activity. The methodology involves the screening of plant products for a specific biological activity, purification of the biologically active natural product by separation technology and structure determination. The biologically active natural products is then further scrutinized to serve as a novel drug or lead compound for the development of a novel drug. This research exploited this research methodology. / South Africa

Fungi are rich sources of structurally diverse secondary metabolites, some of which possess biological activities of importance to medicine and agriculture. Research in our group focuses on application of ecological considerations to the selection of underexplored fungi for chemical analysis in search of new natural products with potentially important bioactivities. The work described in this thesis involved studies of members of two different fungal ecological groups, fungicolous and endophytic fungi. Fungicolous fungi colonize other fungi and are viewed as potential sources of antifungal agents due to the negative effects often exerted on the host organisms. Our prior studies of such fungi have proven them to be productive sources of new bioactive natural products. Fractionation of extracts produced from eleven fungicolous fungal isolates resulted in the isolation and identification of 24 different, structurally-diverse natural products, many of which were bioactive. Most of these were previously known, but six were new compounds, with one being a distinctive new peptaibol-type metabolite. Endophytic fungi colonize the inner tissues of host plants, often asymptomatically, and occur widely in most plant species. Some endophytes may benefit the host, possibly through production of protective secondary metabolites, but in most cases, their roles are not well understood. Stenocarpella maydis is a widely occurring fungal endophyte and pathogen of corn and is associated with diplodiosis (a neuromycotoxicosis) of cattle. Investigations of extracts of S. maydis and S. macrospora cultures led to the identification of seven compounds, including diplodiatoxin, diplosporin, chaetoglobosins K, L, M, and O, and (all-E) trideca-4,6,10,12-tetraene-2,8-diol, none of which were previously known from U.S. Stenocarpella isolates. Diplodiatoxin was detected as a major component of S. maydis-rotted maize grain, stalks, and stalk residues, and chaetoglobosin M was detected in extracts of naturally-diseased S. maydis-rotted maize seeds collected in the field. Chaetoglobosin K displayed potent antifungal and antiinsectan activity, while diplodiatoxin displayed phytotoxicity. Because of their well-known cytotoxic effects, we proposed that mixtures of chaetoglobosins are responsible, at least in part, for inducing diplodiosis in livestock. Our prior investigations of another common corn endophyte, Acremonium zeae, led to isolation of the pyrrocidines, which display potent antifungal and antibacterial activities against a range of corn pathogens. Further studies of these extracts led to the isolation and identification of three resorcylic acid lactone (RAL)-type compounds, one of which was new. These RAL's, did not exhibit antifungal activity, but demonstrated mild phytotoxicity to maize leaves in assays. They are also members of a compound class we have encountered among other endophytes that inhibit the heat shock protein Hsp90, and have been proposed to play a role in the colonization process. These chemical investigations provide further knowledge that may be useful in determining the roles that endophytes, in particular S. maydis and A. zeae, play in maize. The metabolites encountered during these investigations represented different biosynthetic pathways, and included polyketides, terpenoids, and compounds of mixed biogenetic origin. Structures were characterized by analysis of 1D and 2D NMR data, mass spectrometry, chemical degradation or derivatization reactions, and/or X-ray diffraction analysis. Absolute configuration assignments were determined using Mosher's method, Marfey's method, or chiral amino acid analysis methods.

El precio promedio del café se ha incrementado en los últimos años. En el 2018 el precio aumentó hasta en un 8% y se estima un alza adicional de 6% para los siguientes años. Pese a ello, el consumo interno del café también ha aumentado constantemente, teniendo un crecimiento en la frecuencia de compra del café de hasta 22 veces más en el 2018. Los estudios revelan que el incremento en su consumo se debe a que los amantes del café cuentan con mayor poder adquisitivo y además han optado por dar inicio a la búsqueda de un sabor distinto al café tradicional. Atendiendo a esta necesidad de los consumidores de café nace Cafru-it, un concentrado de café mezclado con fruta natural. Como propuesta de valor, Cafru-it ofrece a los consumidores de café un sabor totalmente natural, pues es elaborado a base de granos de café cuzqueño y frutas, las cuales son naranja, durazno y mango. Por otro lado, su consumo es beneficioso para salud por las propiedades de los insumos utilizados para su producción, además de ser un producto eco-friendly, ya que los envases son elaborados de vidrio reciclado y pueden ser reutilizados. El público objetivo esta compuesto por las personas amantes del café que se encuentran en la búsqueda de nuevos sabores y que son estudiantes universitarios o que trabajan en oficinas. Los canales por los cuales Cafru-it se acercará a su público son: redes sociales, página web, ferias ecológicas, venta directa y delivery. / The average price of coffee has increased in recent years. In 2018, the price increased up to 8% and an additional increase of 6% is estimated for the following years. In spite of it, the internal consumption of coffee has also increased steadily, having a growth in the frequency of coffee purchase up to 22 times more in 2018. Studies reveal that the increase in its consumption is due to coffee lovers have greater purchasing power and they have also chosen to start the search for a different flavor than traditional coffee. In response to this need for coffee consumers, Cafru-it is born, a coffee concentrate mixed with natural fruit. As a value proposition, offered to coffee consumers a totally natural flavor, because Cafru-it is made from coffee beans from Cusco and fruits, which are orange, peach and mango. On the other hand, its consumption is beneficial for health due to the properties of the supplies used for its production, in addition to being an eco-friendly product, because the bottles are made of recycled glass and can be reused. The customer segments is composed by coffee lovers who are in search of new flavors and who are university students or who work in offices. The channels through which Cafru-it will approach its customers are: social networks, website, ecological fairs, direct sales and delivery. / Trabajo de investigación

Lo más importante de nuestro proyecto es la propuesta de valor que ofrece Qatiy; así como la cobertura que brinda a cierto sector del mercado que no se encontraba satisfecho o no contaba con alternativas que cumplieran con sus necesidades. Por ello, es importante resaltar la validación del modelo de negocio; pues, si bien la idea puede ser buena, no necesariamente cumple con las expectativas del consumidor. Por esta razón nuestro producto tuvo que ser evaluado minuciosamente para determinar la viabilidad del consumo para su posterior venta. Otro aspecto determinante se basa en el beneficio que nos brinda en términos financieros; es decir, la alta rentabilidad que podemos obtener tras la puesta en marcha de nuestra empresa. El mercado aún se encuentra en desarrollo y los consumidores cada vez tienen nuevos hábitos y concientización de consumo de productos saludables, lo que significan grandes oportunidades para su explotación. Finalmente, hay que destacar que Qatiy incentiva el consumo de productos hecho a base de alimentos saludables que favorece al bienestar del consumidor, ya que se producen con insumos naturales y sin ningún tipo de preservantes, lo cual es un aporte importante de responsabilidad social por parte de nuestra empresa. / The main thing about our project is the value proposition offered by Qatiy; as well as the coverage it provides to a certain sector of the market that was not satisfied or did not have alternatives meeting their needs. Therefore, it is important to highlight; since, while the idea may be good, it does not necessarily meet consumer expectations. For this reason our product had to be thoroughly evaluated to determine the viability of consumption for subsequent sale. Another determining aspect is based on the benefit it gives us in financial terms; that is the high profitability that we can obtain after the start-up of our company. The market is still in development and consumers are acquiring increasingly new habits and are becoming aware of the benefits of healthy products consumption which means big opportunities for exploitation. Finally, it should be noted that Qatiy encourages the consumption of products made from healthy food that favor the well-being of the consumer, since they are produced with natural supplies and without any preservatives; which is an important contribution of social responsibility by our company. / Trabajo de investigación