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" Marine Natural Products: "
Sanchez, Laura Margaret
Linington, Roger G
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Latin Dissertation
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English
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| Record Number
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903353
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TL2wk446nr
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| Main Entry
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Sanchez, Laura Margaret
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| Title & Author
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Marine Natural Products:\ Sanchez, Laura MargaretLinington, Roger G
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| College
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UC Santa Cruz
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| Date
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2012
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| student score
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2012
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| Abstract
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This dissertation describes various aspects of marine natural product chemistry from compound discovery and elucidation to the development of lead scaffolds, and ultimately the use of natural products to probe biological questions. A wide range of techniques are utilized including solid phase peptide synthesis, novel mass spectrometry methods, and vertebrate microbiota to explore the secondary metabolic potential of intestinal flora. In addition to these techniques, various whole cell and bacterial screens were used to identify bioactive compounds. The first chapter provides a historical introduction to marine natural products as drugs leads and chemical probes. The latter half of the chapter discusses a future prospective for the field. Chapters 2 through 4 focus on the almiramide class of natural products isolated from a Panamanian cyanobacteria. The second chapter details the structure activity relationships (SAR) for this class of linear lipopeptides and the selectivity indices against the kinetoplastid parasites Leishmania mexicana and Trypanosoma brucei, and mammalian Vero cells. In chapter 3, synthetic derivatives were derivatitized to create activity based protein profiling probes to elucidate the mechanism of action against T. brucei. Chapter 4 details the use of the almiramide scaffold in conjunction with direct analysis in real time (DART) mass spectrometry to visualize peptides directly from various types of solid supports. The method was extended to include other organic scaffolds and can be used to monitor reaction progress for a number of well know organic transformations. Chapters 5 and 6 examine the use of vertebrate-derived microbiota as a novel source of actinomycetes. The bacteria collected from the stomach contents of various freshly dead commercially available marine fish were phylogenetically analyzed, and in one instance provided a bacteria with 97% sequence identity to its closest culturable bacteria in the National Center for Biotechnology Information database. This bacterium produced a novel bioactive lipid, which displayed activity against both Gram-positive and Gram-negative pathogenic bacteria, as well as, common fish pathogens. In the final chapter, the fish microbiome was assayed in a high content Vibrio cholerae screen to uncover a Rhodoccous sp. which produced a bile acid that modulates biofilm formation in V. cholerae. Secondary biological studies were undertaken to deduce the mechanism by which biofilms were being inhibited.
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Linington, Roger G
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UC Santa Cruz
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