A Theoretical Study of the Reactivity of 5- Fluorouracil toward Superoxide Radical Anion and Hydroperoxyl Radical

Abstract

Abstract The reactivity of 5-fluoro-1H,3H-pyrimidine-2,4-dione (5-fluorouracil), which is widely used to treat cancer, toward superoxide radical anion (O2•−) and hydroperoxyl radical (HO2•) was investigated using density functional theory (DFT) calculations. 5-Fluorouracil is a pyrimidine analog with cytotoxic effects on cancer cells and potential ecotoxicology as a recalcitrant compound to the natural environment, therefore, clarifying its chemical degradation mechanism is difficult by way of in vivo and in vitro experiments but important for further usage. The DFT results clarified that the oxidation of 5-fluorouracil by O2•− or HO2• in water is feasible through a proton-coupled electron transfer (PCET) mechanism. In addition, two PCET pathways are proposed, the initial proton transfer followed by a concerted PCET between 5-fluorouracil and O2•−, and a concerted PCET between 5-fluorouracil and HO2• preformed via the protonation of O2•−. In each pathway, the amine groups at the first and third positions of 5-FU act as reaction sites for the concerted PCET after forming a prereactive complex via a hydrogen bond. Considering that the actual oxidant along the PCET pathways is HO2• with a short lifetime, the biodegradability of 5-FU by O2•− (HO2•) is governed by the complex formation step before the concerted PCET.