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. 2023 Jul 11;15(7):1929.
doi: 10.3390/pharmaceutics15071929.

Synthesis, Characterization, Theoretical and Experimental Anticancer Evaluation of Novel Cocrystals of 5-Fluorouracil and Schiff Bases against SW480 Colorectal Carcinoma

Farhat Jubeen  1 , Ishrat Jabeen  2 , Usman Aftab  3 , Sadia Noor  2   4 , Mah E Hareem  2 , Misbah Sultan  5 , Mohsin Kazi  6
Affiliations

Synthesis, Characterization, Theoretical and Experimental Anticancer Evaluation of Novel Cocrystals of 5-Fluorouracil and Schiff Bases against SW480 Colorectal Carcinoma

Farhat Jubeen et al. Pharmaceutics. .

Abstract

The chemotherapeutic agent known as 5-fluorouracil (5-FU) is an artificial fluoropyrimidine antimetabolite that has been widely used for its antineoplastic properties. Cocrystals of 5-fluorouracil (5-FU) with five different Schiff bases (benzylidene-urea (BU), benzylidene-aniline (BA), salicylidene-aniline (SA), salicylidene-phenylhydrazine (SPH), and para-hydroxy benzylideneaniline (HBA)) are reported in this study. The newly synthesized cocrystals were analyzed by FTIR and PXRD. In this study, we investigated the antitumor efficacy of 5-FU derivatives in SW480 colon cancer cells via MTT assay at varying dose concentrations. Molecular docking was performed to predict the binding mechanism of TS with various 5-FU complexes. FTIR revealed the presence of respective functional groups in the prepared cocrystals. The frequencies (v) of N-H (3220.24 cm-1) and carbonyl groups (1662.38 cm-1) in the spectrum of 5-FU shifted considerably in all derivative cocrystal new interactions. There was a noticeable transformation in the PXRD peak of 5-FU at 2θ = 28.37° in all derivatives. The novelty of the present study lies in the fact that 5-FU-BA showed an anticancer potential IC50 (6.4731) far higher than that of 5-FU (12.116), almost comparable to that of the reference drug doxorubicin (3.3159), against SW480 cancel cell lines, followed by 5-Fu-HBA (10.2174). The inhibition rates of 5-FU-BA and 5-FU-HBA were highest among the derivatives (99.85% and 99.37%, respectively) in comparison with doxorubicin (97.103%). The results revealed that the synthesized 5-FU cocrystals have promising antitumor efficacy compared with previously reported 5-FU and 5-FU. The activities of the cocrystals were rationalized by a molecular modeling approach to envisage binding modes with the target cancer protein.

Keywords: 5-FU; MTT assay; Schiff bases; cocrystallization; computational study.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Structures of Schiff bases synthesized using urea, aniline, and phenyl hydrazine as amines and benzaldehyde, ortho-hydroxy benzaldehyde, and p-hydroxy benzaldehyde as aldehydes.
Figure 1
Figure 1
Proposed mode of interaction between 5-FU and BA Schiff base.
Figure 2
Figure 2
Proposed mode of interaction between 5-FU and the BU Schiff base.
Figure 3
Figure 3
Proposed mode of interaction between 5-FU and the SA Schiff base.
Figure 4
Figure 4
Proposed mode of interaction between 5-FU and the SPH Schiff base.
Figure 5
Figure 5
Proposed mode of interaction between 5-FU and the HBA Schiff base.
Figure 6
Figure 6
PXRD spectral analysis of (a) 5-FU; (b) 5-FU-BA; (c) 5-FU-BU; (d) 5-FU-SA; (e) 5-FU-SPH; and (f) 5-FU-HBA.
Figure 7
Figure 7
Interaction diagram of the protein–ligand complex of TS and 5-FU.
Figure 8
Figure 8
Interaction diagram of the protein–ligand complex of TS and 5-FU-BU.
Figure 9
Figure 9
Interaction diagram of the protein–ligand complex of TS and 5-FU-SA.
Figure 10
Figure 10
Interaction diagram of the protein–ligand complex of TS and 5-FU-SPH.
Figure 11
Figure 11
Interaction diagram of the protein–ligand complex of TS and 5-FU-HBA.
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