Drug Design, Development and Therapy (Jul 2023)
Design, Synthesis and Biological Evaluation of Glycosylated Derivatives of Silibinin as Potential Anti-Tumor Agents
Abstract
Jian-Jun Xi,1,* Yu Cao,1,* Ruo-Yu He,1 Jian-Kang Zhang,2 Yan-Mei Zhao,1 Qiao Tong,1 Jian-Feng Bao,1 Yi-Chen Dong,3 Rang-Xiao Zhuang,1 Jin-Song Huang,1 Yongping Chen,4 Shou-Rong Liu1 1Department of Pharmacy, Hangzhou Xixi Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2School of Medicine, Zhejiang University City College, Hangzhou, People’s Republic of China; 3Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, People’s Republic of China; 4Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Wenzou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongping Chen, Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325025, People’s Republic of China, Email [email protected] Shou-Rong Liu, Department of Infectious Diseases, Hangzhou Xixi Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310023, People’s Republic of China, Email [email protected]: 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 (T1/2 = 128.3 min) in liver microsomes than that of silibinin (T1/2 = 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.Graphical Abstract: Keywords: glycosylation, silibinin derivatives, solubility, anti-proliferative activity
