Cyclodextrin-assisted photostabilization of 5-fluorouracil: a combined kinetic and computational investigation

Abstract

The photostabilization of 5-fluorouracil (5-FU) has been carried out in the pH range of 2.0-12.0 using cyclodextrins (α-, β-, γ-) as a complexing agent. The inclusion complex formation between 5-FU and CDs has been evaluated using conductometry, FTIR spectroscopy, NMR spectroscopy, differential scanning calorimetry (DSC), and molecular docking simulations. The loss of absorbance at 266 nm for 5-FU in the presence of CDs indicates its photodegradation. The entrapment of 5-FU in α-, β-, and γ-CDs ranges from 22.0-58.0, 30.0-64.0, and 42.0-77.0%, respectively, indicating the formation of inclusion complexes of CDs with 5-FU. The values of Stern-Volmer fluorescence quenching constants and binding constants for α-, β- and γ-CDs are 1.10, 1.69, 3.06 × 10³ L mol^-1 and 2.89, 3.11, 3.62 10³ L mol^-1, respectively. The apparent first-order rate constants (k _obs) for the photodegradation of 5-FU in the presence of α-, β-, and γ-CDs are 1.75-5.12, 1.21-4.89, and 0.85-4.69 × 10³, min^-1, respectively. The photochemical interaction (k ₂) of 5-FU with α-, β-, and γ-CDs ranges from 0.25-0.49, 0.63-1.47, and 0.79-2.14 M^-1 min^-1 in the pH range 2.0-12.0. The mode of photochemical interaction of 5-FU and CDs and the photostabilization of 5-FU is described based on H-atom abstraction by 5-FU from CD and radical-radical recombination. The computational analysis complemented the experimental findings, showing a significant second-order donor-acceptor interaction, particularly LP → π*, between the hydroxyl groups of γ-CD and the carbonyl groups of 5-FU. The natural population analysis further revealed a shift in electron density from γ-CD to 5-FU, indicating a protective charge-transfer mechanism that contributes to the photostabilization of 5-FU.

Fig. 1. Chemical structures of 5-fluorouracil (5-FU) (a) and cyclodextrins: (b) α-CD, (c) β-CD, (d) γ-CD.

Fig. 2. FTIR spectra of 5-FU (a), α-CD (b), β-CD (c), γ-CD (d), 5-FU–α-CD (e), 5-FU-β-CD (f), 5-FU-γ-CD (g).

Fig. 3. Spectral changes of 5-FU (5 × 10⁻⁵ M) on photolysis in the presence of CDs (1.25 × 10⁻³ M) (pH 9.0): α-CD (a), β-CD (b), and γ-CD-CD (c).

Fig. 4. ¹H NMR spectra of 5-FU (a), 5-FU-α-CD (b), 5-FU -β-CD (c), 5-FU-γ-CD (d) in D₂O

Fig. 5. Optimized geometry of 5-FU and γ-CD complex (a) and Mulliken population analysis and pictorial representation of atoms by the charge (b), where positive charges are given in green while negative as red, based on their intensities.

Fig. 6. Histogram of Mulliken atomic charges for 5-FU and γ-CD complex.

Fig. 7. 3D illustration of 5-FU inclusion complexes using molecular docking: (a) 5-FU–α-CD (b) 5-FU-β-CD, (c) 5-FU-γ-CD.

Fig. 8. k _obs-pH profiles for the photolysis of 5-FU in the absence (■) and presence of CDs: α-CD (●), β-CD (▲), and γ-CD (♦).