Investigations into the Natural Products of New Zealand Fungi and Synthetic Studies of 6-Substituted Ascididemin Compounds

Abstract

The clinical use of antibiotics revolutionized human medicine but future use of current antimicrobial compounds is limited by widespread bacterial resistance. Two methods towards the discovery of new antimicrobial lead compounds are described in this thesis - natural product screening and directed modification of known lead compounds. Investigations into the natural products of six fungi from Landcare Research's ICMP collection are described. In pre-screening assays these fungi all exhibited antimicrobial activity against at least one of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa or Mycobacterium absessus. Extracts from these fungi were submitted to fractionation in an attempt to isolate and identify active compounds. For most of these fungi, the extracted material was not sufficient for the acquisition of spectral data required for elucidation of compound structures but for one fungus, Penicillium vasconiae, a polyketide metabolite, penicillic acid, was isolated in good yield. Work on this metabolite is described in the third chapter. Dihydro and acetate derivatives of this metabolite were synthesised and tested for antimicrobial activity along with the natural product. Penicillic acid exhibited some inhibitory activity against S. aureus and E. coli as expected based on previous literature but the two derivatives exhibited no activity. Synthetic work on the marine natural product ascididem in is also described. Ascididemin has been shown to have broad-spectrum antimicrobial activity but its usefulness a drug compound is limited by cytotoxicity and poor solubility. The 6-substituted ascididemin analogue, 6-E-styryl ascididemin has a narrower spectrum of activity but possesses greatly reduced cytotoxicity. Analogues of 6-E-styryl ascididemin were prepared with nitro and amino substituents of the styryl ring. 6-Phenethyl ascididemin compounds were also prepared to investigate the effect of molecule planarity on solubility and cytotoxicity. An unexpected synthesis of tetrahydropyrido 6-phenethyl ascididemin compounds offered a new route for the synthesis of ascididemin compounds with selective reduction of ring A.6-(2-Nitro-E-styryl) and 6-(2-amino-E-styryl) ascididemin compounds exhibited considerable inhibitory activity S.aureus (MIC ≤0.25 μg/mL) with no detectable cytotoxic activity. These analogues will provide a new direction in antimicrobial drug discovery.