Identification of a Selective Anticancer Agent from a Collection of Complex-And-Diverse Compounds Synthesized from Stevioside

Compounds constructed by distorting the ring systems of natural products serve as a ready source of complex and diverse molecules, useful for a variety of applications. Herein is presented the use of the diterpenoids steviol and isosteviol as starting points for the construction of >50 new compounds through this complexity-to-diversity approach, featuring novel ring system distortions and a noteworthy thallium(III) nitrate (TTN)-mediated ring fusion. Evaluation of this collection identified SteviX4 as a potent and selective anticancer compound, inducing cell death at low nanomolar concentrations against some cancer cell lines in culture, compared to micromolar activity against others. SteviX4 induces ferroptotic cell death in susceptible cell lines, and target identification experiments reveal SteviX4 acts as an inhibitor of glutathione peroxidase 4 (GPX4), a critical protein that protects cancer cells against ferroptosis. In its induction of cell death, SteviX4 displays enhanced cell line selectivity relative to most known GPX4 inhibitors. SteviX4 was used to reveal dependency on GPX4 as a vulnerability of certain cancer cell lines, not tied to any one type of cancer, suggesting GPX4 inhibition as a cancer type-agnostic anticancer strategy. With its high fraction of sp³-hybridized carbons and considerable cell line selectivity and potency, SteviX4 is unique among GPX4 inhibitors, serving as an outstanding probe compound and basis for further translational development.