5-Fluorouracil-Complete Insight into Its Neutral and Ionised Forms
Justyna Wielińska1, Andrzej Nowacki2, Beata Liberek3
1Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland. justyna.wielinska@phdstud.ug.edu.pl.
Molecules (Basel, Switzerland)
|October 17, 2019
Summary
This study clarifies the ionization states of the anti-cancer drug 5-Fluorouracil (5FU). Computational analysis reveals 5FU exists primarily as a neutral or N1-deprotonated form within physiological pH ranges.
Area of Science:
- Computational Chemistry
- Medicinal Chemistry
- Biochemistry
Background:
- 5-Fluorouracil (5FU) is a widely used anti-cancer drug.
- It exhibits tautomerism and has multiple protonation/deprotonation sites.
- Existing literature presents conflicting information regarding its ionized forms.
Purpose of the Study:
- To perform comprehensive theoretical studies on the neutral, protonated, and deprotonated forms of 5FU.
- To resolve contradictions in the literature regarding 5FU ionization states.
- To determine the dominant tautomeric and ionization forms of 5FU under various conditions.
Main Methods:
- Density Functional Theory (DFT) methods were employed for complex theoretical calculations.
- Natural Bond Orbital (NBO) and Electron-Spin Resonance (ESP) analyses were used to assess charge delocalization.
- pKa values were calculated to predict ionization states across different pH ranges.
Main Results:
- In the gas phase, O4 is preferentially protonated and N1 is preferentially deprotonated.
- Solvation effects in aqueous phases reduce stability differences between protonated/deprotonated forms.
- Calculated pKa values indicate 5FU is not protonated or doubly deprotonated between pH 0-14.
Conclusions:
- The neutral form of 5FU predominates below pH 8.
- The N1-deprotonated form of 5FU becomes dominant above pH 8.
- These findings clarify the ionization behavior of 5FU, crucial for understanding its drug action.
