Reactivity-Guided Isolation and Medicinal Chemistry of Marine Bacterial Natural Products

Marine natural products have long served as leads for pharmaceutical compounds, as well as sources of compounds whose value lies in the novelty of their structures. As more natural products are discovered and described, compounds with truly novel structures or bioactivities have become increasingly difficult to find. Therefore, a reactivity-guided approach has been developed to aid in the search for natural products bearing specific functional groups. An azide-based probe for terminal alkyne-bearing natural products was synthesized and implemented, which facilitated the discovery of the vatiamide family of natural products. Further, a suite of tetrazine-based probes for isonitrile-bearing natural products was synthesized and evaluated on the basis of reactivity, stability, and fragmentation behavior in mass spectrometry. The marine bacterial natural product lymphostin was recognizable for its unusual structural features, but its biochemical activity, and mechanism thereof, was not fully understood. Lymphostin and its family of related analogs were evaluated for their kinase inhibition activity, and model systems were synthesized to understand lymphostin’s mechanism of kinase inhibition. Lymphostin was found to be a potent and irreversible inhibitor of PI3K/mTOR, the first compound from bacteria to be shown with this activity. An effort towards the total synthesis of lymphostin was then undertaken, resulting in the discovery of an unusual heteroaryl dimerization reaction