Exploring the chemical space around austdiol by semi-synthesis

Natural products provide structurally diverse chemical scaffolds with applications in pharmaceuticals and agrichemicals. However, many natural products do not possess PK/PD properties suitable for direct application as chemotherapeutic agent. When isolated material is sufficient, semi-synthetic modification of a natural product scaffolds is a useful technique for exploring chemical space around a pharmacophore to improve bioactivity and druggability. In this thesis, chemical derivatisation was used to expand the chemical space around austdiol, a toxic azaphilone first isolated in 1973 from the fungus Aspergillus ustus. A small semi-synthetic library of fourteen austdiol analogues was synthesised, focusing primarily on degradation, reduction, oxidation and amination reactions. Their structures were determined by HRESIMS and spectroscopic methods, including NMR and UV-vis. These derivatives were screened for antibacterial, antifungal, and cell cytotoxic activities. Finally, a 2,4-dinitrophenylhydrazone derivative of austdiol was explored as a chiral derivatisation agent to assist in the resolution of L and D enantiomers of amino acids commonly found in natural products, by UV-vis detection in reversed-phase liquid chromatography.