Orthogonality in Natural Products Workflows

In 1969 Weinheimer and Spraggins reported the isolation of prostaglandins from the gorgonian coral Plexaura homomalla. This was a remarkable discovery for being one of the first reports of a marine natural product and for its significance to human health, where prostaglandins were being studied for their obstetric effects. It foreshadowed a new pipeline of drug discovery from the oceans; as well as highlighting many difficulties of drug discovery in general, and specific problems of working with marine samples. The isolation of a compound of interest from P. homomalla demanded that questions be asked about sustainability and ecology; were there other sources of the prostaglandins to be discovered, could this species be cultured or harvested sustainably? Further work on P. homomalla revealed a minor analog, 5-trans-15(S)-PGA2, demonstrating one of the most persistent problems in natural products chemistry, the presence of compounds that are difficult or impossible to detect at the low concentration which they are found in nature. Decades later, with thousands of marine natural products reported from sources across the tree of life, many of these problems still exist. New analytical tools have been developed, and old ones have become far more sensitive, but this has not erased these difficulties. In fact they have often simply shown that the unexpected diversity of biologically active compounds produced below the previous limit of detection. Every tool and technique developed, or improved, to survey the metabolome offers new data, but none provides a complete picture. To be successful a natural products workflow must incorporate the concept of `orthogonality', application of multiple overlapping and complementing techniques to provide a more comprehensive survey of the target metabolome. The work in this dissertation exemplifies this concept, where the study of various cyanobacterial strains began with one technique, such as NMR structure guided isolation, which led to another, such as mass spectrometry fragmentation analysis, when new tools became necessary to describe an organism's metabolic capacity. This work has revealed novel compounds, shown unprecedented diversity in known families of compounds, and improved our understanding of the mechanism of action of an active compound