Design, synthesis, and biological evaluation of RSL3-based GPX4 degraders with hydrophobic tags.

Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation, during which glutathione peroxidase 4 (GPX4) plays an essential role and is well-recognized as a promising therapeutic target for cancer treatment. Although some GPX4 degradation molecules have been developed to induce ferroptosis, the discovery of GPX4 degraders with hydrophobic tagging (HyT) as an innovative approach is more challenging. Herein, we designed and synthesized a series of HyT degraders by linking the GPX4 inhibitor RSL3 with a hydrophobic and bulky group of adamantane.

Deciphering the Diversified Metabolic Behavior of Hydroxyalkyl Ferrocidiphenols as Anticancer Complexes.

Ferrocidiphenols possessing appropriate substituents in the aliphatic chain have very promising anticancer properties, but a systematic approach to deciphering their diversified metabolic behavior has so far been lacking. Herein, we show that a series of novel ferrocidiphenols bearing different hydroxyalkyl substituents exhibit strong anticancer activity as revealed in a range of and experiments. Moreover, they display diversified oxidative transformation profiles very distinct from those of previous complexes, shown by the use of chemical and enzymatic methods and and metabolism studies.