Sulfur and selenium antioxidants: Challenging radical scavenging mechanisms and developing structure–activity relationships based on metal binding

•Metal coordination is key to preventing oxidative DNA damage at low concentrations.•ROS scavenging primarily occurs at non-biological concentrations.•Selenium compounds prevent DNA damage more effectively than sulfur compounds.•Thiones and selones prevent DNA damage through multiple mechanisms.

Because sulfur and selenium antioxidants can prevent oxidative damage, numerous animal and clinical trials have investigated the ability of these compounds to prevent the oxidative stress that is an underlying cause of cardiovascular disease, Alzheimer's disease, and cancer, among others. One of the most common sources of oxidative damage is metal-generated hydroxyl radical; however, very little research has focused on determining the metal-binding abilities and structural attributes that affect oxidative damage prevention by sulfur and selenium compounds. In this review, we describe our ongoing investigations into sulfur and selenium antioxidant prevention of iron- and copper-mediated oxidative DNA damage. We determined that many sulfur and selenium compounds inhibit CuI-mediated DNA damage and that DNA damage prevention varies dramatically when FeII is used in place of CuI to generate hydroxyl radical. Oxidation potentials of the sulfur or selenium compounds do not correlate with their ability to prevent DNA damage, highlighting the importance of metal coordination rather than reactive oxygen species scavenging as an antioxidant mechanism. Additional gel electrophoresis, mass spectrometry, and UV–visible studies confirmed sulfur and selenium antioxidant binding to CuI and FeII. Ultimately, our studies established that both the hydroxyl-radical-generating metal ion and the chemical environment of the sulfur or selenium significantly affect DNA damage prevention and that metal coordination is an essential mechanism for these antioxidants.

Graphical abstractSulfur and selenium antioxidants prevent metal-mediated oxidative DNA damage at biological concentrations primarily by metal coordination. Metal binding changes the metal redox properties and allows targeted scavenging of reactive oxygen species.Figure optionsDownload full-size imageDownload as PowerPoint slide