Design, Synthesis and Biological Evaluation of Glycosylated Derivatives of Silibinin as Potential Anti-Tumor Agents

Abstract

Objective: Silibinin, a natural product extracted from the seeds of the Silybum marianum, is versatile with various pharmacological effects. However, its clinical application was strongly hampered by its low bioavailability and poor water solubility. Herein, a series of glycosylated silibinin derivatives were identified as novel anti-tumor agents.

Materials and methods: The cell viability was evaluated by CCK8 assay. Furthermore, cell apoptosis and cell cycle progression were tested by flow cytometry. In addition, the pharmacokinetic assessment of compound 15 and silibinin through intravenous administration (i.v., 2 mg/kg) to ICR mice were performed.

Results: The synthesized compounds showed better water solubilities than silibinin. Among them, compound 15 exhibited inhibitory activity against DU145 cells with IC₅₀ value of 1.37 ± 0.140 μM. Moreover, it arrested cell cycle at G2/M phase and induced apoptosis in DU145 cells. Additionally, compound 15 also displayed longer half-life (T_1/2 = 128.3 min) in liver microsomes than that of silibinin (T_1/2 = 82.5 min) and appropriate pharmacokinetic parameters in mice.

Conclusion: Overall, glycosylation of silibinin would be a valid strategy for the development of silibinin derivatives as anti-tumor agents.

Keywords: anti-proliferative activity; glycosylation; silibinin derivatives; solubility.

Graphical abstract

Figure 1

Chemical structures of respective components of silymarin.

Figure 2

The design strategy of glycosylated derivatives of silibinin.

Scheme 1

Synthesis of silibinin derivatives 14–15.

Scheme 2

Synthesis of silibinin derivatives 16–17.

Figure 3

The UV–Vis spectra of the target compounds 14–17 and silibinin in H₂O.

Figure 4

Apoptosis rate and cell cycle of DU145 cells treated with compound 15 or silibinin. DU145 cells were treated with compound 15 (3, 10, 30 μM) or silibinin (30 μM) for 24 hours. (A) Flow cytometry. (B) Cell cycle analysis by propidium iodide staining. (C) Quantitative analysis of apoptotic cells. (D) The percentage of cell cycle distribution. Results were mean ± SD for three individual experiments. **p < 0.01.

Figure 5

Plasma concentration vs time curves after iv (2 mg/kg) administration of compound 15 and silibinin to mice. Data are represented as the mean ± SD (n = 3).