Biotechnology

Organic chemistry

In vivo

In silico

Mechanism of action

Oxidative stress

Lead compound

Membrane

Biology

Gene

Biophysics

Apoptosis

Chemistry

In vitro

Antioxidant

Lipid peroxidation

Phospholipid

Drug

Programmed cell death

Lipid bilayer

Toxicity

Biochemistry

Pharmacology

Journal of Medicinal Chemistry

Ferroptosis is an iron-catalyzed, nonapoptotic form of regulated necrosis that results in oxidative lipid damage in cell membranes that can be inhibited by the radical-trapping antioxidant Ferrostatin-1 (Fer-1). Novel inhibitors derived from the Fer-1 scaffold inhibited ferroptosis potently but suffered from solubility issues. In this paper, we report the synthesis of a more stable and readily soluble series of Fer-1 analogues that potently inhibit ferroptosis. The most promising compounds (37, 38, and 39) showed an improved protection compared to Fer-1 against multiorgan injury in mice. No toxicity was observed in mice after daily injection of 39 (UAMC-3203) for 4 weeks. UAMC-3203 inserts rapidly in a phospholipid bilayer in silico, which aligns with the current understanding of the mechanism of action of these compounds. In conclusion, these analogues have superior properties compared to Fer-1, show in vivo efficacy, and represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models.

Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy