UC Santa Cruz

The application of natural products to newly identified phenotypic and target-based screens is central to the drug discovery process. Currently the research and development (R&D) process for a drug can span 10 – 15 years which includes the discovery, development, and final application of the therapeutic. This dissertation aims to describe the progression of 3 compounds along our internal R&D process. Chapter 1 presents a perspective on how natural products have impacted our fundamental understanding of chemicals structure and reactivity. It finishes by highlighting lead compounds in the area of HIV latency and bacterial biofilm inhibition. Chapter 2 describes the discovery, structural assignment, and biological annotation of abyssomicin 2 as a reactivating agent of latent HIV. Subsequent studies showed the mechanism of action (MOA) was not PKC activation or HDAC inhibition, which suggests a novel MOA. Chapter 3 addresses the development of quinoline amino alcohols as disruptors and dispersal agents of V. cholerae biofilms. This has led to the discovery of a lead compound, which future studies aim to integrate as the bioactive component for medical implant devices. Chapter 4 highlights the application of the TBADT/NFSI fluorination reaction to the recently reported bile acids, which have been identified as V. cholerae biofilm inhibitors. These studies identified N-Me taurine analogs with improved activity and fluorinated analogs with reduced activity highlighting key structure activity relationships for these compounds.