First-principles insights into tegafur to 5-FU conversion driven by H+ ion in the presence of Na+, K+ ions, and water molecule

In this study, we employ first-principles calculations to investigate the mechanism of tegafur prodrug conversion to 5-Fluorouracil (5-FU), the active anticancer agent. To achieve this, the adsorption of H⁺ ion on tegafur is investigated, considering the role of acidity as a key factor and one of the distinctive properties of cancer cells. The results indicate that the most stable configuration of H⁺ ion adsorption is directly associated with the conversion of tegafur to 5-FU. To enhance the accuracy of our calculations, the adsorption of Na⁺, K⁺ ions, and water molecule is also examined, and the potential for tegafur conversion to 5-FU in the presence of these species is evaluated. The findings revealed that these species alone are incapable of breaking down tegafur, highlighting the stability of this prodrug in the bloodstream. Furthermore, the simultaneous adsorption of these species alongside H⁺ ion is investigated. The results demonstrated that under these conditions, H⁺ ion is adsorbed, leading to the conversion of tegafur to 5-FU. Based on the obtained results, it can be concluded that the reduced side effects of tegafur, compared to 5-FU, are attributed to its selective conversion to 5-FU in the acidic microenvironment of cancer cells rather than in healthy cells. This selective activation mechanism underscores the therapeutic advantage of tegafur as a prodrug in cancer treatment.