By the turn of the 21th century, it became evident that even microorganisms intensely studied as sources of natural products contained the DNA instructions to produce many more compounds than those that were being extracted. Thus, in order to tap into this source of novel natural products, which could serve as structural leads for the development of new drugs against emerging diseases like cancer and multi-resistant bacterial infections, new methods are urgently needed. In this work, a method dubbed “reactivity-guided isolation” is investigated as a drug discovery approach for different classes of natural products: 1) electrophilic natural products, a therapeutically-relevant class of natural products that covalently modifies their cellular targets, 2) conjugated alkene-containing natural products, a characteristic moiety found in natural products of polyketide origin, and 3) isocyanide-containing natural products, a functional group associated with the biological activity observed in various sponge metabolites. Using carefully designed chemoselective reagents, the method forms derivatives of these different classes of natural products that are UV-active and highly conspicuous via mass spectrometry (MS) by virtue of an isotopically-unique bromine or chlorine tag. Throughout development and application of this method we have expanded the toolbox for derivatizing natural products (and the reagents) and in the process we have synthesized high-value derivatives from high yielding coupling reactions; we have gain insight into the use of UV and MS tags and crystallization units for X-ray analysis that provide opportunities to simplify detection and structural elucidation of natural products; and we have discovered new natural products entities from microorganisms grown in the laboratory, and in some cases predict how they might interact with cellular components. The work presented here has the potential to streamline natural product discovery platforms and lead to new compounds useful in the treatment of diseases.

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.