UC Santa Cruz

Natural products research has had a significant impact on human-health and our understanding of the natural world as a pillar of pharmacognosy, organic chemistry, ecology, and chemical biology. But while this science has yielded countless discoveries such as penicillin, taxol, and artimesinin and will continue to improve quality of life around the world, the idea that natural products is a panacea of chemical diversity has been challenged by problems including the endless rediscovery of known compounds, the immense time required to isolate and elucidate structures, and the need for large amounts of scarce compounds to exceed the ever raising bar of biological annotation for drug approval. This thesis will provide examples of the use of integrated biological and chemical annotation of natural product libraries for the comprehensive functional annotation of natural product libraries, a new platform to expedite the dereplication and structural assignment of natural products libraries, and a study using genome annotation tools to look at the diversity of secondary metabolite biosynthetic gene clusters across a large set of cultured bacterial clades. Each chapter will discuss how using these modern techniques enabled the discovery of the quinocinnolinomycins (3.1-3.4), the elucidation of the aryl-polyenes (APEEC and APEVF), and the deeper understanding of the biological effects and constitution of natural products libraries through the dereplication of phencomycin. The net result of all these technologies is that they change natural products research from an intensely focused effort to discover the most potent compounds for a particular disease, to a hypothesis and data driven exploration of the subtle interactions of secondary metabolites within biological settings.