LAUSR

Antioxidant therapy is a promising treatment strategy for protecting DNA from the damage caused by reactive oxygen species (ROS). Here, we report new self‐cyclizing antioxidant reagents that are selective for the hydroxyl radical. Our mechanistic investigation revealed that the reagents react with three equivalents of oxidant in a cascade reaction to form a bicyclic final product. Among the reagents synthesized, 1 c showed favorable properties in vitro and in cellular studies. Using As2O3, which triggers ROS production, we showed that 1 c prevents formation of the guanine oxidation product 2,2,4‐triamino‐2H‐oxazol‐5‐one‐2′‐deoxyribonucleoside and lowers cellular levels of reactive oxygen. The described self‐cyclizing antioxidants are efficient, flexible, and tunable reagents with the potential to limit toxic oxidative stress.