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Reactivity-guided isolation of marine and bacterial natural products in the genomic age


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.

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