| Natural products have historically been a rich source for therapeutics and therapeutic leads. In particular, the marine environment has offered a virtually untapped resource for unique chemical scaffolds with therapeutic potential. Despite the success of natural products in the development of therapeutics, the hit-to-lead process still remains a major bottleneck in drug development. Chemical rediscovery, as well as the challenges of structure elucidation, have historically been major obstacles in the discovery of novel natural products. This dissertation explores methods to minimize these obstacles, and novel natural products with therapeutic potential are presented as a result of these methods.;To address the obstacles of chemical rediscovery, LCMS-based metabolomics was used as a tool for bacterial strain selection. Principal component analysis (PCA) of LCMS data from marine-derived bacterial extracts allowed for a spatial distribution of the chemistry produced. PCA allowed for selection of bacterial strains (WMMB499, WMMB215), and subsequent fermentation, isolation, and structure elucidation led to 12 novel structures (peptidolipins B-F, halomadurones A-D, ecteinamycin, and forazolines A and B). To address the challenges of structure elucidation, a method of 13C incorporation and subsequent acquisition of 13C-13C COSY NMR allowed for rapid structure elucidation of bacterial-derived natural products (ecteinamycin and forazoline A).;Most importantly, the 17 novel natural products presented in this dissertation demonstrated a vast array of therapeutic potential, including antibacterial (peptidolipins B-F and ecteinamycin), anti-cancer (thiocoraline and novel analogs), anti-neurodegenerative (halomadurones A-D), and antifungal (forazolines A and B) activity; forazoline A demonstrated in vivo efficacy. Additional work is necessary for these compounds to continue down the drug development pipeline, but overall, they provide an example for the utility of methods, such as LCMS-based metabolomics and 13C-labeling of bacterial-derived natural products, for improving the efficiency of the hit-to-lead process. Ultimately, the novel structures presented in this dissertation reinforce the potential of the marine environment as a source for therapeutics and therapeutic leads. |
