Structure, Synthesis and Biological Activity of Harmful Algal Bloom Toxins from Karlodinium sp. and Exploration of Microbial Derived Natural Products

This work features natural products isolated from both the marine and microbial environments. Part I focuses on the elucidation of toxins from harmful algal blooms (HAB). The HAB dinoflagellate <italic>Karlodinium veneficum</italic> produces a harmful suite of molecules identified as the karlotoxins (KmTx) that have been implicated in massive fish kills pan-globally. Nine new karlotoxin congeners were isolated from various <italic>Karlodinium</italic> blooms around the world and utilizing the structure of KmTx2 were characterized using overlaid 2D NMR techniques. Due to the contrasting conformational differences between KmTx and the closely related amphidinols, the absolute configuration of KmTx was further evaluated by extensive computational analysis of the <italic>J</italic>-based coupling constants (<italic>J</italic>BCA) and chemical shifts (CS) of the <super>1</super>H and <super>13</super>C NMR data. In addition, the total synthesis of one congener is being attempted to obtain additional material for biological studies and further structure activity relationship (SAR) studies. The expanded SAR of the class is being explored for new insights for agents for the treatment of cancer and as angiogenesis inhibitors. Part II focuses on the isolation and characterization of novel lactone lipids, scoriosin and its methyl ester, isolated from <italic>Scorias spongiosa</italic>, a fungus that is commonly referred to as sooty mold and can be found growing on both <italic>Fagus sylvaticus</italic> and <italic>Fagus grandifolia</italic>, better known as the European and American beech trees. Using a combination of calculated and experimental electronic circular dichroism (ECD) and CS analysis, the absolute configuration of the molecules was established. Both compounds displayed antimicrobial and antifungal activity with IC₅₀ values in the low µM to high nM range for <italic>Cryptococcus neoformans</italic>, <italic>Staphylococcus aureus</italic> and methicillin-resistant <italic>Staphylococcus aureus</italic> (MRSA). The second project in Part II focuses on using matrix assisted laser desorption ionization- mass spectrometry (MALDI-MS) imaging to confirm production of key pharmaceutical precursor secondary metabolites from marine associated bacteria. Through microbial community analysis, optimization of fermentation conditions and MALDI-MS imaging, the first report of a sponge-associated bacterium (<italic>Micromonospora</italic> sp. M42) from the Indo-Pacific sponge <italic>Acanthostrongylophora ingens</italic> (Thiele, 1899) that produces the manzamine class of antimalarials is presented.

Name thesis:degree_name

Ph.D. in Pharmaceutical Sciences

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomolecular Sciences

Year dc:date.available

2014

Author dc:creator

• Waters, Amanda Leigh

Contributors dc:contributor

• Mark T. Hamann
• Stephen J. Cutler
• Allen R. Place

• Dinoflagellate
• Harmful Algal Blooms
• MALDI-MS Imaging
• Marine Natural Products
• Microbial Natural Products
• Structural Elucidation
• Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://egrove.olemiss.edu/etd/1504

OAI identifier oai:identifier

oai:egrove.olemiss.edu:etd-2503