ABSTRACT
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.
Subject(s)
Apoptosis , Glutathione Peroxidase/physiology , Iron/chemistry , Animals , Carbolines/chemistry , Cell Line, Tumor , Colorimetry , Dioxolanes/chemistry , Endoplasmic Reticulum/metabolism , Glutathione/chemistry , Glutathione Peroxidase/chemistry , Homeostasis , Humans , Lipid Peroxidation , Mice , Microsomes/metabolism , NADP/chemistry , Oxidative Stress , Phospholipid Hydroperoxide Glutathione Peroxidase , Piperazines/chemistry , Protein Engineering , Structure-Activity RelationshipABSTRACT
The isolation and characterization of a trans-oxasilacycloheptene is reported. Single-crystal X-ray crystallographic studies indicate a high level of strain and deviation from ideal geometry. Reactions with several electrophiles demonstrated the nucleophilicity of the C=C double bond, affording oxasilacycloheptane and tetrahydrofuran products as single diastereomers.
ABSTRACT
The cobalt-catalyzed peroxidation of silyl enol ethers with molecular oxygen and triethylsilane provided silyl monoperoxyketals in 54%-96% yield. These compounds serve as precursors to peroxycarbenium ions, which undergo annulations to provide 1,2-dioxolanes.
Subject(s)
Cobalt/chemistry , Dioxolanes/chemical synthesis , Ethers/chemistry , Silanes/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Cyclization , Dioxolanes/chemistry , Silanes/chemistryABSTRACT
By using (N-tosyloxy)-3-O-carbamoyl-D-glucal 10, which removes the need for a hypervalent iodine(III) oxidant, we provide evidence for rhodium nitrenoid-mediated ipso C-H activation as the origin of a C3-oxidized dihydropyranone product 3. This system may be especially susceptible to such a pathway because of the ease of forming a cation upon hydride transfer to the rhodium-complexed acyl nitrene.
