New Deferric Amine Compounds Efficiently Chelate Excess Iron to Treat Iron Overload Disorders and to Prevent Ferroptosis

Abstract

Excess iron accumulation occurs in organs of patients with certain genetic disorders or after repeated transfusions. No physiological mechanism is available to excrete excess iron and iron overload to promote lipid peroxidation to induce ferroptosis, thus iron chelation becomes critical for preventing ion toxicity in these patients. To date, several iron chelators have been approved for iron chelation therapy, such as deferiprone and deferoxamine, but the current iron chelators suffer from significant limitations. In this context, new agents are continuously sought. Here, a library of new deferric amine compounds (DFAs) with adjustable skeleton and flexibility is synthesized by adopting the beneficial properties of conventional chelators. After careful evaluations, compound DFA1 is found to have greater efficacy in binding iron through two molecular oxygens in the phenolic hydroxyl group and the nitrogen atom in the amine with a 2:1 stoichiometry. This compound remarkably ameliorates iron overload in diverse murine models through both oral and intravenous administration, including hemochromatosis, high iron diet‐induced, and iron dextran‐stimulated iron accumulation. Strikingly, this compound is found to suppress iron‐induced ferroptosis by modulating the intracellular signaling that drives lipid peroxidation. This study opens a new approach for the development of iron chelators to treat iron overload.

The Role of Oxidative Stress in TB Meningitis and Therapeutic Options

“…Despite posing health risks such as gastrointestinal symptoms and agranulocytosis, DFP is better than DFO since it penetrates the lipid membrane more efficiently, eliminating iron overload and decreasing the risk of continued oxidative stress [ 62 , 63 ]. Finally, DFX, orally administered, has shown better results than DFO and DFP [ 64 ]. The highest recommended dosage is 30 mg/kg per day, and it is given in one of two forms: DFX film-coated tablets (FCT), a newly approved form, or DFX dispersible tablets (DT).…”

The role of Hippo pathway in ferroptosis

“…Since ferroptosis is caused by the excessive production of lipid ROS, the application of antioxidants such as ferrostatin-1, trolox, butylated hydroxytoluene, and tert butyl hydroxyanisole can eliminate lipid ROS, thereby inhibiting the process of ferroptosis. In addition, since the lipid oxidation process requires the participation of ferrous ions, the application of iron ion–chelating agents such as desferrilamine and cyclopidone can reduce the production of lipid ROS, thereby inhibiting ferroptosis ( 61 ) ( Figure 2 ).…”

Mechanism of action of ferroptosis and its role in liver diseases

“…Iron chelators are compounds that bind to iron, reducing the accumulation of toxic ROS and lipid peroxides. Several iron chelators, including deferoxamine and deferiprone, have been shown to inhibit the sensitivity of cells to ferroptosis [4]. On the other hand, overexpression of ferritin can protect against ferroptosis [5].…”