Navigating Dipeptide by a Nucleoside Moiety: A Promising Way for Enhancing Antioxidative Effect against Radical-Induced DNA Oxidation

Construction of novel antioxidants against radical-induced oxidation of DNA is still challenging, though we have elucidated that the Ugi four-component reaction (Ugi 4CR) acts as an efficient way for achieving antioxidative dipeptides with caffeic, ferulic, sinapic, and syringic acids being the antioxidative functional groups. Herein, as an ongoing exploration on the designing of nucleoside-appended antioxidants, dipeptides accessed from the Ugi 4CR are applied for the connection with 5′-OH of a nucleoside moiety with a succinate being the linkage. Antioxidative effects of the afforded nucleoside-appended dipeptides are enhanced 2∼3-fold compared to their parent dipeptides when they are used to protect DNA against the peroxyl-radical-induced oxidation. This is ascribed to the introduction of a nucleoside moiety into the antioxidative dipeptide enabling navigation of the dipeptide to intercalate with the DNA strand more tightly, and the hydroxy and amino groups in the nucleoside moiety are beneficial for the nucleoside-appended dipeptide to scavenge radicals. Thus, the navigation of Ugi 4CR products by a nucleoside moiety is shown to be a versatile approach for accessing novel antioxidants that are able to protect DNA against radical-induced oxidation more efficiently.