UC San Diego

Plants, animals, and microorganisms produce an incredible variety of biologically active natural products, which are the result of secondary metabolism. Many of these molecules are highly toxic to a variety of cell types and organisms. Scientists have exploited these properties for decades to create effective anti-cancer, anti-fungal, anti -bacterial and anti-viral agents that have saved millions of lives. However, until the 1990s, comparatively little effort had been invested in tapping into this resource of bioactive small molecules for the discovery of compounds that act by other, non-toxic means. The areas of asthma research and the underlying issue of allergic inflammation are two of these areas that have received relatively scant attention from natural products scientists. Recent advances in immunology, cellular, and molecular biology have begun teasing apart the pathways and mechanisms involved in allergic inflammation, making assay development for drug discovery feasible. This thesis aims to describe a new approach to screen natural products for their ability to inhibit allergic inflammation. Chapter one provides an overview of asthma and allergic inflammation as well as describing past natural products remedies and current drug therapies. Chapter two details the rationales and methodologies implemented in the development of a biological assay used to screen for compounds in extracts of marine microbial cultures that inhibit the production of pro-inflammatory molecules. It includes the results from a screen of 2,500 microbial extracts as well as discussions regarding previously reported molecules shown to be active in the assay, nuisance compounds, and collaborative efforts with others in the Fenical Laboratory that resulted in novel activity for exciting new marine bacterial natural products. Chapter three centers on a new group of molecules called the splenocins that were isolated from extracts of the marine actinomycete bacterial strain CNQ431. Included are the isolation, structure elucidation, and in vitro results for these molecules which were the most potent to be isolated thus far. Chapter four discusses the isolation, structure elucidation and cytokine inhibition activity of two novel nor-diterpenes isolated from a different marine actinomycete bacterium