Technology and Biodiscovery: Using Modern Technologies and Methods to Tackle the Challenges of Biodiscovery

Leith Fremlin (2011). Technology and Biodiscovery: Using Modern Technologies and Methods to Tackle the Challenges of Biodiscovery PhD Thesis, Institute for Molecular Bioscience, The University of Queensland.

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Author Leith Fremlin
Thesis Title Technology and Biodiscovery: Using Modern Technologies and Methods to Tackle the Challenges of Biodiscovery
School, Centre or Institute Institute for Molecular Bioscience
Institution The University of Queensland
Publication date 2011-12
Thesis type PhD Thesis
Supervisor Professor Robert Capon
Dr. Andrew Piggott
Total pages 297
Total colour pages 189
Total black and white pages 111
Language eng
Subjects 0301 Analytical Chemistry
0305 Organic Chemistry
Abstract/Summary Modern natural products chemistry draws upon biodiversity from terrestrial and marine environments with the challenge to isolate bioactive molecules. In order to answer this challenge, natural products chemists utilise an arsenal of modern separation techniques to isolate the compounds of interest, followed by modern spectroscopic methodologies to elucidate the compounds structure and chemical properties. The introduction reviews the use of the hyphenated technique, LC-(SPE)-NMR, in natural products research. The following chapters are accounts of three different research projects undertaken on a terrestrial Streptomyces sp., a marine Aspergillus versicolor isolate, and a variety of cephalopod species. Chapter 2 presents the use of LC-SPE-NMR for the isolation and characterisation of a series of novel analogues belonging to a family of [5,6]- and [6,6]-spiroketal polyketides known as the reveromycins. The Streptomyces sp. isolate (MST-RA7781) used in this study was found to be a large producer of the reveromycins including 11 previously unreported analogues. The challenge to isolate these compounds was not trivial, which lead to the use of LC-SPENMR methods. Furthermore, the observation of a single 'contaminant' peak associated with the hemi-succinate [6,6]-spiroketal reveromycins has prompted a discussion whether the [5,6]–spiroketal reveromycins and hemi-succinate 4'-methyl ester reveromycins are natural products or isolation artefacts. Chapter 3 focuses on two new cyclic pentapeptides, the cotteslosins, and five known compounds isolated from a marine-derived Aspergillus versicolor isolate (MST-MF495). The introduction to this chapter reviews marine cyclic peptides of which more than 30 have been reported to date. Whilst the cotteslosins did not possess appreciable biological activity, they are closely related to a group of anticancer depsipeptides known as the sansalvamides prompting a discussion on structure activity relationships and proposing that chemical modifications to the cotteslosins may result in compounds with higher biological activity. The structures of all seven compounds were solved through the use of NMR experiments, whilst Marfey's analysis was employed to solve the absolute stereochemistry of the cyclic peptides. During the use of the Marfey's analysis, a number of limitations were observed - particularly around the resolution of the isoleucine isomers which prompted the development of a new C3 Marfey's method. Chapter 4 includes a review highlighting the methods used to solve the absolute configuration of natural peptides including the Marfey's analysis and the limitations of the differing methods. A large number of isolated natural peptides has been presented including any reported biological activity. Surprisingly, for a large number of compounds there was no attempt to solve the absolute configuration of the substituent amino acids. Compounds were also uncovered where the Marfey's analysis had been successfully used to solve the absolute configuration of the amino acids whilst failing to address the issue of allo- amino acid stereoisomers, or a second analytical procedure was required to address this issue. The development of a new C3 Marfey's method is presented which allows for the stereochemistry of all proteogenic amino acids to be solved in a single HPLC analysis. The new method has been successfully applied to the cotteslosins and acremolides. Chapter 5 details the initial studies on the chemistry of Australian cephalopods and includes a through review of the chemistry of cephalopods, including isolated toxins, pigments, peptides and proteins, lipids, steroids, and ink. A number of specimens were utilised in this study including Hapalochlaena sp. (blue-ringed octopus), Sepioloidea lineolata (striped pyjama squid), Metasepia pfefferi (flamboyant cuttlefish), Octopus (Abdopus) sp. (droparm octopus) and Octopus (Octopus) cyanea (day octopus) all isolated from Australian waters and subjected to various bioassays and separation strategies. Whilst ongoing, this preliminary study has laid the groundwork for further research into the chemistry of Australian cephalopods.
Keyword Natural Products Chemistry
Cyclic Peptide
Additional Notes Colour pages: 11-12, 43-62, 65, 69-71, 73-74, 77-81, 83-104, 106-111, 113-115, 117-122, 124-127, 129-131, 136-148, 150-164, 166-167, 172, 174-191, 193, 195, 197, 199-208, 210-211, 213-218, 220, 222-227, 229, 231-232, 237-238, 240-243, 245, 247-260, 272-280

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Created: Mon, 23 Apr 2012, 18:58:13 EST by Mr Leith Fremlin on behalf of Library - Information Access Service