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Natural compounds have been largely excluded from characterization via high-throughput profiling strategies due to their limited abundance. Herein, I describe the modification of high-throughput yeast chemical genomic (CG) interaction profiling to permit identifying the modes of action of natural compounds. The previous assay proceeded by evaluating the genome-wide yeast deletion collection for drug-hypersensitivity in a volume of 0.7mL. Compound consumption was minimized with the adapted approach by reducing the assay volume 70% through simplifying the complexity of the yeast deletion pool screened. By recreating each yeast mutant in a drug-hypersensitive background, I created a novel resource that increases compound efficiency and further diminishes compound use. Evaluating a series of characterized compounds analyzed previously by the traditional CG approach validated the adaptations incorporated did not negatively affect the quality of data yielded. Ultimately, this modified strategy will be used to screen thousands of natural compounds contained within the RIKEN NPDepo library.

Major depressive disorder affects people’s productivity and ability to function in everyday life. The disorder can be attributed to neurochemical imbalances of various neurotransmitters including but not limited to serotonin, dopamine, and norepinephrine. Conventional pharmacological treatments have focused primarily on these three neurotransmitters, and have been shown to be effective in alleviating most of the major symptoms of depression. Although these treatments are effective with most patients, they are known to have adverse side effects, causing patients to seek alternative treatments. Sceletium tortuosum, a succulent plant found in the Cape region of South Africa, has been shown to have anxiolytic effects when used recreationally. Studies have confirmed the presence of a family of alkaloids mesembrines that are present within the plant and believed to be responsible for the calming effects. Pharmacological analyses have revealed that individual members of the alkaloid family act as either serotonin reuptake inhibitors (SRI) or phosphodiesterase-4 (PDE4) inhibitors. The current study seeks to elucidate the antidepressant properties of the mesembrine alkaloids in a mouse model of depression. Isolated alkaloids were administered at a low dose (10 mg/kg) and a high dose (80 mg/kg) to BALB/c mice in the forced swim test a rodent model of behavioral despair. This was compared with paroxetine (Paxil) (1 mg/kg), a selective serotonin reuptake inhibitor with proven antidepressant efficacy, and 0.9% saline. Each trial of the forced swim test was administered for six minutes and the duration of swimming and immobility was measured. In order to assess any locomotor effects of the drug treatments, an open field exploration test was also employed one week following the forced swim task. Results from the forced swim test revealed a statistically significant reduction in the duration of immobility (behavioral despair) between the low dose of alkaloids and saline. No significant effects in immobility were found across the other drug treatment conditions (high dose mesembrine, paroxetine, and saline). Further, none of the treatment groups showed statistically significant locomotor interference effects in the open field exploration test. We conclude that the mesembrine alkaloids present in Sceletium tortuosum have antidepressant properties and may represent a suitable alternative for the treatment of major depressive disorder.

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.

Isolation and structure elucidation of natural products from marine sponges and an invertebrate were performed. The marine sponges and invertebrate were obtained from three locations including South East Queensland, in Australia, Pontianak in West Kalimantan, and Tulamben, in Bali, Indonesia. The natural products were purified using chromatographic techniques, the structures were elucidated by means of extensive 1D and 2D NMR spectroscopy and some were confirmed by X-ray crystallography. Five known compounds and potentially a new metabolite were identified from three different sponges and a species of nudibranch obtained in Mooloolaba, South East Queensland in Australia. Furospinosulin-1 (4.5), a linear sesterterpenoid, was identified from a sponge coded 20-1-07-1-7 while imidazole alkaloids, preclathridine A (4.9) and clathridine (4.10), were characterized from sponge 22-4-07-2-1. The ethyl acetate extract of sponge 14-7-07-1-1 yielded a polyacetylene fulvinol-like compound (4.15) and potentially a new metabolite compound 5 (4.21). Additionally, a specimen of Chromodoris kuiteri furnished a cyclic macrolide latrunculin A (4.27). There were six secondary metabolites identified from Aaptos aaptos, two of which to the best of our knowledge were new compounds. Aaptamine (5.1), a chemotaxonomic marker of the sponge A. aaptos, 9-demethylaaptamine (5.3) and a biosynthetically unrelated compound (-)-jaspamide (5.31) were found as major constituents of the dichloromethane extract of the sponge. On the other hand, a known indole-3-carbaldehyde (5.10), and the two new natural products methyl 3-(8,9-dimethoxy-4H-benzo[de][1,6]naphthyridin-4-yl)propanoate (5.11) and 8,9-dimethoxy-4H-benzo[de][1,6]naphthyridine-5,6-dione (5.30) were isolated as minor components. During a two-month fieldwork trip to Tulamben, Bali, six different sponges were obtained. Investigation of a blue colored sponge Petrosia sp. afforded two isoquinolinequinone metabolites, namely mimosamycin (5.35) and O-demethylrenierone (5.36). A new 3-alkylpiperidine metabolite, tetradehydrohaliclonacyclamine A (6.28), was isolated from a sponge Halichondria sp. The structure and relative stereochemistry of 6.28 were determined from analysis of 2D NMR data and interpretation of coupling constants. Suitable crystals that were grown from hexane: ethyl acetate (1:3) allowed the determination of the absolute configuration of 6.28 and it was established to be 2S, 3S, 7S, and 9S on the basis of X-ray crystallographic data. The isolated compound (6.28) appeared to be as a single enantiomer according to chiral HPLC. The parent compounds, haliclonacyclamine A (6.19) and B (6.20), were re-isolated from a sample (coded BK-Hal-12-AIK) obtained from a previous project on Haliclona in our group. Their absolute configurations were determined for the first time by X-ray crystallography and they were established to be 2R, 3R, 7R, and 9R.

Compounds from the marine environment exhibit a wide variety of biological activities, and thus hold much promise as potential drugs. The halichondrins, isolated from the Kaikoura sponge Lissodendoryx sp. are no exception to this, demonstrating potent anticancer activity. Novel cytotoxic compounds have also been isolated from the Chatham Rise sponge Lamellomorpha strongylata. Knowledge of the cellular origins of such compounds is desirable, in order to establish if the sponge or associated micro-organisms are producing the compounds of interest. Siderophores are also important molecules, which are produced on demand by bacteria in order to obtain sufficient iron necessary for their growth. Knowledge of the biosynthesis of these compounds has potential for the control of undesirable bacteria, such as the anthrax-causing pathogen Bacillus anthracis. Cell separation studies have been carried out on Lamellomorpha strongylata, locating a swinholide in sponge-associated filamentous bacteria and theonellapeptolides in sponge-associated unicellular bacteria. A microscopic analysis of dissociated cells from Lissodendoryx sp. was also undertaken. The structures of four new halichondrins (3.13 - 3.16), isolated from Lissodendoryx sp., have been determined from spectral data. All of these compounds are very similar to known B series halichondrins, with differences occurring only beyond carbon 44. As biological activity has been shown to be derived from the portion of the molecule between carbons 1 and 35, they all retain good activity in the P388 assay as expected. A new siderophore, petrobactin sulfonate (4.2), was characterised, along with three cyclic imide siderophore derivatives (4.3 - 4.5). Petrobactin sulfonate is the first marine siderophore containing a sulfonated 3,4-dihydroxy aromatic ring. The structures were elucidated from spectral data, resulting in a revision of the NMR assignments of petrobactin.

Thesis (Ph. D.)--University of Canterbury, 2007. / Typescript (photocopy). Includes bibliographical references. Also available via the World Wide Web.

Thesis (Ph.D. (Chemistry)) - Rhodes University, 2008.

Thesis (Ph.D.) -- McMaster University, 2005. / Supervisor: I. L. Bourgeault. Includes bibliographical references.

Thesis (Ph. D.)--University of California, San Diego, 1998. / Vita. Includes bibliographical references (p. 223-227).