High-throughput screening (HTS) is the primary driver to current drug discovery efforts. New therapeutic agents that enter the market are a direct reflection of the structurally simple compounds that make up screening libraries. Unlike medically relevant natural products (e.g., morphine), small molecules currently being screened have low fraction sp3 character and few, if any, stereogenic centers. Although simple compounds have been useful in drugging certain biological targets (e.g., protein kinases), more sophisticated targets (e.g., transcription factors) have largely evaded the discovery of new clinical agents from screening collections. Here, we describe a tryptoline ring distortion strategy that enabled the rapid synthesis of 70 complex and diverse compounds from yohimbine 1, an indole alkaloid. The compounds that were synthesized had architecturally complex and unique scaffolds, unlike 1 and other scaffolds. These compounds were subjected to phenotypic screens and reporter gene assays leading to the identification of new compounds that possess various biological activities, including: antiproliferative activities against cancer cells with functional hypoxia inducible factors, nitric oxide inhibition, inhibition and activation of the antioxidant response element (ARE). This tryptoline ring distortion strategy can begin to address diversity problems in our screening libraries while occupying biologically relevant chemical space in areas critical to human health.

DNA-encoded libraries are usually screened against tagged proteins to identify ligands, but many other screening modalities either have been, or likely will be, developed that expand the utility of these libraries as a source of bioactive molecules.

Bacterial biofilms are surface-attached communities of bacteria that are: (1) highly prevalent in human infections, and (2) resistant to conventional antibiotic treatments and host immune responses.