The chemical diversification of natural products provides a robust and general method for creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.

The International Younger Chemists Network (IYCN) is an organization that aims to connect chemists who are in the early stages of their career, including but not limited to graduate school, postdoctoral associates, chemists within five years of their terminal degree, and chemists newly transitioning into the field. Our core objective is to reach like-minded scientists globally and create a platform for scientific exchange. With a focus on building a worldwide network, we strive to spread scientific knowledge, mentorship, and encourage a passion for chemistry.

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