Chemical Forays of Fungal Metabolites

This thesis contains six chapters and the research presented within focuses on three parts. The first part (chapter one to three) was the isolation of antibacterial and antioxidant mushroom metabolites, and the synthesis towards analogues of discovered natural products. The following part (chapter four) was to assess antioxidant activities of synthetic compounds and investigate their SAR (structure-activity relationship), by use of a developed DPPH assay. The last part (chapter five to six) was the discovery of an abiotic halogenation reaction among a class of fungal metabolites, azaphilones. A series of their synthetic analogues were applied as model compounds to understand the mechanism of the discovered unusual and facile non-enzymatic nucleophilic halogenation reaction. Chapter one is a review of antioxidants in mushrooms. The components with antioxidant activities discovered from mushrooms were summarised by their chemical structures and representative samples were listed. In addition, the potential mechanisms of those antioxidants were described in this chapter. In chapter two, extracts of 20 mushrooms from PNG (Papua New Guinea) were screened against both Gram-positive and Gram-negative bacteria, six of them were chosen as chemical survey candidates for their strong antibacterial activities. Extracts of 37 PNG mushrooms were screened for their antioxidant using a modified DPPH assay, 14 of them were chosen as chemical survey candidates based on their antioxidant capacities. In chemical examination guided by bioactivity, five natural products including two novel furan fatty acids (2.1-2.2) and three known compounds, i.e. grifolin (2.3), grifolic acid (2.4) and grifolic acid methyl ether (2.5), were isolated from four selected mushroom samples. Chapter three described the synthetic efforts towards analogues of three isolated antioxidant fungal metabolites (2.3-2.5). Inspired by 15 synthetic targets, a short and versatile general synthetic route was established to deliver 40 compounds possessing structures related to the natural products. Based on these structures, a compound library was established for antioxidant assessment in the following SAR research. The synthetic work resulted in the preparation of 33 novel structures. In chapter four, various antioxidant assays and their working mechanisms were reviewed, as well as their corresponding advantages and drawbacks. A developed DPPH assay was optimised to offer an accurate and reproducible antioxidant evaluation for SAR research in the achieved compound library. The results indicated that a structure with an aromatic ring to be allylated with a carbon chain in addition to the presence of phenols, is required to show an antioxidant activity, and the increased length of a carbon chain (more prenyl units) enhances the antioxidant activity. Chapter five focused on naturally occurring organohalogen compounds with biotic origins. The representative halogenated natural products with a variety of bioactivities were categorised following a chemical structural classification as well as a bioactive classification, to showcase both their structural diversity and bioactive variety. The biosynthetic mechanisms of halogenated natural products were reviewed in this chapter. Chapter six detailed the investigation of a novel halogenation reaction that was discovered to be occurring with some azaphilone fungal metabolites, for example the conversion of (+)-deschlorosclerotiorin (6.2) into (+)-sclerotiorin (6.1). Various non-halogenated model compounds with an azaphilone core structure were created to shed light on the authenticity of numerous halogenated azaphilones reported as natural products. The ensuing synthetic work resulted in an efficient general procedure producing the required targets. The following investigation of the halogenation revealed a novel, facile, non-enzymatic nucleophilic reaction and its proposed mechanism is discussed. The synthetic efforts resulted in the creation of 22 novel structures