Expanding non-natural chemical space through synthetic diversification of natural product extracts

Natural products are structurally diverse compounds that often possess biological activity, making them the most prominent source for the discovery and development of drugs. Existing discovery methods often lead to the re-discovery of known compounds, causing the pharmaceutical industry to deprioritize natural products as a source of drug leads. Examination of natural products chemical space indicates that there are gaps that have yet to be filled in, suggesting that new methods are needed expand chemical space to access novel chemistry. This work expands chemical space by using synthetic transformations to derivatize natural product extracts. A library of 540 prefractionated derivatized natural product extracts was generated and screened against bacterial pathogens and cancer cells. A change in the antimicrobial and anticancer activity was observed as a result of the derivatizations. Derivatization of extract via a strain release reaction produced a novel staurosporine derivative with increased activity against human osteosarcoma cells.