This thesis described the chemical investigations of natural products from Australian marine sponge-derived fungi. Sponge samples were collected from the Great Barrier Reef, Queensland, Australia, by Queensland Museum. The thesis is divided into eight chapters and can be devided into two major parts. The first three chapters comprised the first part of the thesis: Chapter 1 outlined the research background, literature review of marine fungal secondary metabolites; Chapter 2 introduced fungal culture and storage background knowledge, and the list of isolated marine fungal strains. Chapter 3 introduced the background of the thrombin inhibition assay and assay results. The second part (Chapter 4 to 7) of this thesis is focused on chemical isolation and structure elucidation of secondary metabolites from isolated fungal strains, mostly active strains against thrombin. An unidentified fungal strain, FS-G315858 (T)-Y, isolated from the frozen sponge sample Dysidea sp.1400 produced five peptide compounds (chapter 4, 16-20). Compound 16 is a polypeptide which features the same relative configuration with a known compound unguisine A, and compounds 17-20 are diketopiperazines. Active fungal strains FS-G315695 (T)-Y and FDPS-61732-YB were isolated from different sponge samples. However, they were identified to be the identical fungal strain Eurotium rubrum; the chemical isolation of FS-G315695 (T)-Y from its mycelia EtOAc extract resulted in three compounds (chapter 5, 17-19). Compounds 18 and 19 were identified to be flavoglaucin and iso-dihydroauroglaucin. Compound 17 was identified to have the same relative configuration with a known compound neo-echinulin A. The chemical isolation of FDPS-61732-YB from its broth EtOAc extract resulted in several diketopiperazines (chapter 5, 27-29). Another active fungal strain FS-G315695 (T)-WY was identified as Aspergillus ochraceous, the chemical isolation of its mycelia EtOAc extract resulted in one benzodiazepine compound (chapter 6, 18), together with two fatty acids (chapter 6, 16-17). The structure of compound 18 was elucidated and identified to have same relative configuration with the known compound circumdatin E. Media comparison for active fungal strain FS-G315695 (T)-Y was conducted and this work resulted in producing several neo-echinulin analogues (chapter 7, 1-3). The isolation and structure elucidation of these compounds were reported in chapter 7.

This dissertation describes the isolation of secondary metabolites from natural origins through a series of chromatographic techniques and spectrometric characterization in the effort of drug discovery. The isolated compounds obtained were used as drug leads against tropical diseases, namely malaria and leishmaniasis. While first chapter offers an introduction on the use of a natural product by itself as an effective therapeutic and its role on inspiring the discovery of new drugs, the later chapters will concentrate on isolation and characterization of bioactive natural products from an Antarctic sponge and mangrove endophytic fungi during the dissertation work. The second chapter describes the attempt to develop a new method of solving the absolute configuration of tertiary alcohol using lanthanide chiral shift reagent and 13C NMR spectroscopy. The third chapter describes the isolation of five new steroids, norselic acids A-E, from Crella sp. collected in Antarctica. The structures of the norselic acids were established by NMR and MS techniques. The absolute stereochemistry of norselic acid A was elucidated by SXRD. The antimicrobial and anti-leishmania activities of norselic acid A have been studied. Norselic acid A displays antimicrobial activities against methicillin-resistant S. aureus (MRSA), S. aureus, E. faecium, and C. albicans. Norselic acids B-E exhibit mild antimicrobial activities. All norselic acids exhibit strong cytotoxicity against leishmania. The fourth and fifth chapters describe a Medicine for Malaria Venture (MMV) funded malaria bioassay-guided screening program. The chemical investigation of the crude endophytic fungal extracts has led to the isolations of a series of known cytochalasins along with the discovery of a few new compounds, including a new simple carboxylic acid, and several known and novel compounds belonging to the dimeric xanthone family. Majority of the cytochalasins display mild cytotoxicity and outstanding inhibition to chloroquine-resistant reference strain Plasmodium falciparum (W2) with IC50 ranging from 25.8 nM to 2900nM. However, their cytostatic properties hinder them from being a good drug candidate. The dicerandrols display good activity with the lowest IC50=0.63 μM against malaria with low cytotoxicity. The structures of the compounds isolated and the associated anti-malarial activities are reported herein.