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Novel selenium compounds as potent inhibitors of ferroptosis

Affiliation
Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Karl-von-Frisch-Str. 2, 35043 Marburg, Germany
Merkel, Melanie;
Affiliation
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany
Matheo, Saurin;
Affiliation
Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Karl-von-Frisch-Str. 2, 35043 Marburg, Germany
Matzkeit, Marie;
Affiliation
Marburg Center of Mind, Brain, and Behavior – CMBB, Hans-Meerwein-Straße 6, 35032 Marburg, Germany
Nickel, Antonia;
Affiliation
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany
Peter-Ventura, Alejandra M.;
Affiliation
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany
Schlitzer, Martin;
Affiliation
Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Karl-von-Frisch-Str. 2, 35043 Marburg, Germany
Culmsee, Carsten

Ferroptosis is a caspase-independent form of regulated cell death, characterized by iron-dependent accumulation of reactive oxygen species (ROS), primarily through lipid peroxidation and mitochondrial ROS formation1. Decreased activity of glutathione peroxidase 4 (GPx4) and increased lipoxygenase (LOX) activation are established triggers of ferroptosis. The seleno-enzyme GPx4 plays a crucial antioxidative role by reducing lipid hydroperoxides, thereby interrupting the lipid peroxidation chain reaction. The synthetic organoselenium compound ebselen mimics the antioxidant role of GPx4 and is under investigation for the treatment of various diseases.

This study introduces novel selenium compounds derived from ebselen and assesses their potential for ferroptosis inhibition in neuronal HT22 cells. The novel selenium compounds demonstrated enhanced protective activity against both erastin- and RSL3-induced oxidative cell death compared to the scaffold compound ebselen. The protective effects were observed in a time- and concentration-dependent manner on ferroptosis hallmarks, including lipid peroxidation, ROS production, and mitochondrial disruption. The structurally modified selenium compounds exhibited robust protection at concentrations tenfold lower than ebselen. Remarkably, the diselenides, featuring two identical molecules linked by a selenium-selenium bond, displayed significantly stronger protective effects compared to the respective benzisoselenazole compounds,
surpassing predictions based on the calculated molarity. The pronounced protective effects of these novel selenium compounds underscore their potential as innovative therapeutic candidates for attenuating ferroptosis.

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