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Chlorination of 5-Fluorouracil: Reaction Mechanism and Ecotoxicity Assessment of Chlorinated Products

5-Fluorouracil (5-FU) is a pyrimidine antimetabolite introduced in the clinic as an anticancer drug. The reaction between 5-FU and hypochlorous acid (HOCl) is the fundamental process which can occur in activated neutrophils in cancer patients [1] or during chemical treatment of wastewaters [2]. This study combines synthesis, NMR and MS spectroscopy, quantum chemical calculations, and toxicity experiments on Daphnia magna to investigate chemical fate of 5-FU in chlorinated environment. All structures were fully optimized with the B3LYP functional. The standard 6-31+G(d) basis set was used for geometry optimizations and frequency calculations. Improved energetics have been calculated using B2K-PLYP functional and 6- 311+G(3df, 2p) basis set. Gibbs energies of solvation were determined using the SMD continuum solvation model at the B3LYP/6- 31+G(d) level (ε = 78.4). Two explicit water molecules were found as „the ideal number of solvent molecules” for a reliable description of the corresponding potential energy surfaces. The first chlorinated product chlorohydrin 3a was less toxic than the parent 5-FU, suggesting the beneficial effect of chlorination (Figure 1). Further chlorination leads to N1- chlorinated intermediate 6, that undergoes pyrimidine ring opening reaction. The final product 11 was obtained after the loss of the chlorinated urea fragment. This is the most potent compound in the reaction sequence, with toxicity parameter EC50 more than twice lower compared to the parent 5-FU. Interplay between experimental and theoretical procedures, to properly describe reaction pathways and provide more information on toxicity profiles, is a way forward in environmental science research. [1] C. C. Winterbourn, A. J. Kettle and M. B. Hampton, Ann. Rev. Biochem. 85 (2016) 765- 792. [2] J. L. Acero, F. J. Benitez, F. J. Real and G. Roldan, Water Res. 44 (2010) 4158-4170.

5-fluorouracil ; chlorination ; quantum-chemical methods ; ecotoxicological analysis

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