FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation.

Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc- or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.

Diastereoselective peroxidation of derivatives of Baylis-Hillman adducts.

Cyclic derivatives of Baylis-Hillman adducts were synthesized. Cobalt-catalyzed peroxidation of these cyclic lactones afforded silyl peroxides in diastereomeric ratios ranging from 91:9 to 97:3.

Synthesis of Enantiopure Triols from Racemic Baylis-Hillman Adducts Using a Diastereoselective Peroxidation Reaction.

Using a chiral (-)-menthone auxiliary, enantiopure cyclic derivatives of Baylis-Hillman adducts were synthesized. A diastereoselective peroxidation reaction was used to introduce an oxygen atom and establish another stereocenter. The resulting products could be elaborated by employing a one-flask reduction-acetylation protocol followed by a diastereoselective nucleophilic substitution reaction. Removal of the (-)-menthone auxiliary provided an enantiopure triol with a structure related to naturally occurring polyols.