Theoretical elucidation of the reaction mechanisms of 5-fluorouracil-induced oxidative damage to biomolecules

Abstract 5-Fluorouracil (5-FU) is an antineoplastic drug used in the treatment of cancer and dermatological conditions; however, it has been reported to have adverse effects. This research elucidates the adverse effects associated with oxidative stress, observed with this anticancer drug due to its oxidizing effects on biomolecules, such as proteins, lipids, and DNA. Here, a theoretical analysis of the oxidizing activity of the 5-FU on biomolecules using density functional theory with the M05-2X functional, the 6-311+g(d,p) basis set, and a continuous solvation model, in aqueous and lipid environments, is presented. The mechanism of the oxidizing action on biomolecules has been elucidated, demonstrating that it occurs via electron and formal hydrogen atom transfer. The greatest damage has been observed in the protein models of tyrosine, cysteine, and tryptophan, with rate coefficients on the order of 10 9 M −1 s −1 . DNA damage is identified at the 2-deoxyguanosine molecule at Δ G ° r = 4.42 kcal/mol. Regarding lipid damage, it has been found that it is 14.82 times slower than the lipid peroxidation rate, and it is observed that in the protein models of histidine and leucine, no damage occurs. This research is expected to contribute to the understanding of the damage that this anticancer agent can cause to biological systems.