Development of an iron-selective antioxidant probe with protective effects on neuronal function

Iron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinsońs and Alzheimer's diseases, Friedreich ataxia and Huntington's disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1, 3-dihy-droxy-2-(hydroxymethyl) propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl) acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitroand in cells. CT51 bound Fe²⁺ with high selectivity and Fe³⁺ with somewhat lower affinity. Cyclic voltammetric analysis revealed irreversible binding of Fe³⁺ to CT51, an important finding since stopping Fe²⁺/Fe³⁺ cycling in cells should prevent hydroxyl radical production resulting from the Fenton-Haber-Weiss cycle. When added to human neuroblastoma cells, CT51 freely permeated the cell membrane and distributed to both mitochondria and cytoplasm. Intracellularly, CT51 bound iron reversibly and protected against lipid peroxidation. Treatment of primary hippocampal neurons with CT51 reduced the sustained calcium release induced by an agonist of ryanodine receptor-calcium channels. These protective properties of CT51 on cellular function highlight its possible therapeutic use in diseases with significant oxidative, iron and calcium dysregulation.