Chemistry and Bioactivity Studies of Australian Microorganisms

Ratnayake, Ranjala (2007). Chemistry and Bioactivity Studies of Australian Microorganisms PhD Thesis, , University of Queensland.

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Author Ratnayake, Ranjala
Thesis Title Chemistry and Bioactivity Studies of Australian Microorganisms
Institution University of Queensland
Publication date 2007
Thesis type PhD Thesis
Supervisor Professor Robert Capon
Abstract/Summary Australia is recognized as one of the few megabiodiverse countries in the world. Included within Australia’s rich biodiversity are the microorganisms, of which only a fraction have been examined from a chemical perspective. In this respect, both terrestrial and marine microorganisms are largely untapped resources. The introduction to the thesis (Chapter 1) reviews natural products isolated from Australian microorganisms associated with both marine and terrestrial environments. The chemistry and biological activities of a wide range of structure classes isolated from Australian microbial sources during the period from 1970- 2006 are presented herein. The remainder of the thesis describes the investigation of one terrestrial, one marine-derived fungal species and an actinomycete. Chapter 2 discusses an investigation of the fungus Aspergillus unilateralis (MST-F8675) leading to a series of new dipeptides, aspergillazines A-E and the known compound trichodermamide A. The aspergillazines incorporate a selection of unprecedented heterocyclic systems. Aspergillazine A proved to be a sulphur containing metabolite while aspergillazines B and C were isomeric reduced analogues, also bearing sulphur. Aspergillazines D and E were oxygen analogues of the latter compounds that re-equilibrated to a ~1:1 mixture on standing. The structure elucidation of aspergillazines A-E was carried out by detailed spectral analysis. Chapter 3 details the investigation of a marine derived fungus, Acremonium sp. (MF558a) the extract of which displayed significant cytotoxic activity. Fractionation yielded known cytotoxic chaetoglobosins plus a series of new cyclic lipodepsipeptides, acremolides A-D. All acremolides incorporate a common proline, with variations focusing around a single amino acid residue (Val, Ile, Phe) and the oxidation level of the functionalized fatty acid residue. Chemical derivatizations of acremolides A and B were carried out to facilitate both structure elucidation and biological assays. The existence of both cis and trans isomers of proline in all of the acremolides was established by 1H and 13C NMR studies. The amino acid sequence was confirmed by gHMBC correlations while absolute configuration of the amino acids was determined by Marfey’s analysis. The acremolides belong to a family of new lipodepsipeptides represented by a single reported compound in 2002. They also feature close structural resemblance to several tetrapeptides known to be potent histone deacetylase (HDAC) inhibitors, which will be addressed in this chapter. The cytotoxic activity shown by the crude extracts was determined to be due to the known metabolites 19-Oacetylchaetoglobosins D and B. Chapter 4 discloses chemical and biological profiling of an isolate of the rare actinomycete genus Kibdelosporangium (MST-108465) revealing an array of structurally diverse metabolites some of which displayed potent and selective cytotoxic properties. Detailed examination revealed the cytotoxic metabolites as belonging to a new class of heterocyclic polyketides, exemplified by kibdelones A-C. Kibdelone A possess a unique heterocyclic system featuring a 􀀁-pyrone, a substituted pyridone and quinone/hydroquinone motifs. The co-metabolites, isokibdelones A-C and the kibdelonic acids were also discovered. Interestingly, the isokibdelones reveal an unexpected "twist" in the polyketide biosynthesis leading to novel heterocyclic skeleton. The kibdelonic acids represent fully aromatized biosynthetic precursors to the kibdelones. The kibdelones and isokibdelones undergo redox equilibration under suitable conditions and a possible mechanism for this process has been proposed. Kibdelones A-C exhibit potent (nM) and selective cytotoxicity against a panel of human tumor cell lines, and are currently under consideration as potential anticancer lead compounds. This chapter presents the isolation and structure elucidation of these novel polyketides and provides a discussion on their chemistry, biological activity and biosynthetic origins.

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Created: Fri, 21 Nov 2008, 15:14:28 EST