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A theoretical study of the reactivity of 5-fluorouracil toward superoxide radical anion and hydroperoxyl radical

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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, a concerted PCET pathway between 5-fluorouracil and HO2• preformed via the protonation of O2•− is proposed. In this pathway, the amine group at the first position of 5-fluorouracil acts as a reaction site 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-fluorouracil by O2•− (HO2•) is governed by the complex formation step and the concerted PCET.

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All data generated or analyzed during this study are included in this published article and its supplementary materials.

Abbreviations

DFT:

Density functional theory

PCET:

Proton-coupled electron transfer

ROS:

Reactive oxygen species

PT:

Proton transfer

ET:

Electron transfer

SET:

Single-electron transfer

HAT:

Hydrogen-atom transfer

B3LYP:

Becke three-parameter Lee–Yang–Parr

M06-2X:

Minnesota 06

HOMO:

Highest occupied molecular orbital

LUMO:

Lowest unoccupied molecular orbital

PCM:

Polarized continuum model

NBO:

Natural bond orbital

NH:

Amine group

SOMO:

Singly occupied molecular orbital

PRC:

Prereactive complex

HB:

Hydrogen bond

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Acknowledgements

The authors would like to thank Yuki Mori for his experimental assistance.

Funding

This research was funded by Iwatani Naoji Foundation, Research Foundation for the Electrotechnology of Chubu, and a Grant-in-Aid for Scientific Research, grant number 19K16338, from the Japan Society for the Promotion of Science (JSPS).

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  1. Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan

    Tatsushi Nakayama

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Correspondence to Tatsushi Nakayama.

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Nakayama, T. A theoretical study of the reactivity of 5-fluorouracil toward superoxide radical anion and hydroperoxyl radical. Struct Chem 35, 65–73 (2024). https://doi.org/10.1007/s11224-023-02248-3

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