Diversity-oriented synthesis is a strategy that can be used to efficiently produce chemical libraries that exhibit large skeletal diversity and span a large portion of chemical space. Such libraries are well-suited for chemical screening and have produced a number of useful chemical probes. In this context, photochemical reactions are appealing for their ability to generate chemical complexity in a single chemical step. Herein we describe a pathway whereby pyridinium salts undergo Wilzbach–Kaplan photoelectrocyclization to afford vinyl aziridine cores, which are further elaborated to generate compounds with rigid, bicyclic cores. In an initial screen of patient-derived pancreatic organoids, one of these bicyclic ureas was found to exhibit cell-line-specific cytotoxicity. Testing of additional analogs in multiple cell lines revealed structure-activity relationships and activity stratification between enantiomers, validating the initial hit. Additional experiments will be performed to elucidate the molecular target.

Photochemistry-derived small molecules exhibit cell-line-specific toxicity in pancreatic cancer models

256th National Meeting (2018)

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