UC Santa Cruz

As new diseases and drug resistance emerge, the biomedical sciences need to increase resources in drug discovery and development. A key contributor to drug discovery is natural products research. Scientists look to Nature to find cures for diseases and inspiration for new and interesting chemistry. Natural Products (NPs) have proven to be vital resources for therapeutic development of antibiotic, antifungal, and anticancer drugs and are validated sources of tool compounds, compounds that can provide insight into biological systems. While advances in the field have led to innovation in drug discovery, in recent years there have been greater challenges in isolating novel NPs. Compounds have been progressively reisolated from different sources, so new approaches are necessary to continue to discover novel biologically relevant compounds. To overcome this challenge, new chemical and biological approaches are needed to drive discovery. My work focused on the use of 11B NMR (nuclear magnetic resonance) spectroscopy to guide the isolation of boronated NPs.Boron is a highly abundant element and is essential for plants and animals. Despite the essentiality and widespread availability of boron, its functional role in biological systems is poorly understood. Research into boron-containing compounds has been limited by the lack of analytical tools available to study them. Our lab recently optimized a 11B NMR method to allow for the efficient and effective study of small amounts of boronated metabolites in crude material. This method allows us to not only look for novel boron-containing natural products but also probe the role of boron in biological systems. Discussed here are three areas of interest regarding analysis of boron: 1) The use of 11B NMR to guide the isolation of di-adenosine borate from a microbial extract. 2) The optimization of the 1H-11B HMBC NMR experiment to analyze small amounts of biologically derived material. 3) The use of untargeted LCMS-based metabolomics to observe differential regulation of small molecules in wildtype (col-0) and high boron requiring mutant (bor1-1) Arabidopsis thaliana plants in response to different levels of boron supplementation to probe the role of boron in plant function. Separately, this dissertation also discusses the use of different isolation approaches for the purification of secondary metabolites. First, high throughput screening for NSCLC activity and cytotoxicity-guided purification resulted in the isolation and identification of a glycosterol. Second, a metabolomics molecular networking platform allowed for mass-guided isolation of the antimicrobial metabolite amicoumacin C.