Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities

Abstract

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.

Graphene Quantum Dots Inhibit Lipid Peroxidation in Biological Membranes

“…For example, Balakrishnan and Kenworthy revealed that lipid peroxidation changes the partitioning of membrane embedded proteins . Therefore, there has been an emerging interest to mechanistically understand how lipid peroxidation can be suppressed. , One specific type of biological membrane that is rich in PUFA content is the inner mitochondrial membrane (IMM). The generation of excess reactive oxygen species (ROS) near the IMM can contribute to mitochondrial dysfunction as oxidation causes permeabilization of the IMM and loss of mitochondrial membrane potential. − Cardiolipin (CL) is a primary component of the IMM, and it is crucial for maintaining mitochondria structure and morphology .…”