Drug Design, Development and Therapy (Dec 2019)
Synthesis of Novel Xanthone Analogues and Their Growth Inhibitory Activity Against Human Lung Cancer A549 Cells
Abstract
Junqi Wu,1,2,* Jinwei Dai,1,3,* Yuyang Zhang,1,3 Jing Wang,1 Lei Huang,1 Hongmei Ding,1 Tiejun Li,1,4 Yuefan Zhang,1,5 Junqin Mao,6 Shichong Yu1 1College of Pharmacy, Naval Medical University, Shanghai 200433, People’s Republic of China; 2Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China; 3Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China; 4Department of Pharmacy, Punan Hospital, Shanghai 200125, People’s Republic of China; 5Biomedical Innovation R&D Center, School of Medicine, Shanghai University, Shanghai, 20444, People’s Republic of China; 6Department of Pharmacy, Shanghai Pudong New Area People’s Hospital, Shanghai 201299, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junqin Mao Email [email protected] Yu Tel/Fax +86-21-81871228Email [email protected]: Xanthones demonstrated an array of pharmacological activities via non-covalent DNA interaction and have been widely utilized in new drug research. The introduction of the polar 1,2,3-triazole ring located at the C3-position of xanthone has not been reported thus far.Methods: In the present study, a series of xanthone derivatives were designed, synthesized, and characterized through 1H NMR, 13C NMR, and MS. The methyl thiazolyl tetrazolium method was used to evaluate the cytotoxic activity of compounds. Furthermore, the structure–activity relationship and the potential mechanism of target compounds were investigated.Results: The IC50 showed that the inhibitory activity of 18 target compounds was higher than that of the original xanthone intermediate 4. In particular, compound 1j was the most active agent against A549 cancer cells (IC50 = 32.4 ± 2.2 μM). Moreover, apoptosis analysis indicated different contributions of early/late apoptosis to cell death for compounds 1h and 1j. The results of Western blotting analysis showed that compound 1j significantly increased the expression of caspase 3, Bax, and c-Jun N-terminal kinase, and regulated p53 to a better healthy state in cancer cells.Conclusion: We synthesized several derivatives of xanthone and evaluated their cytotoxicity. The evidence suggested that compound 1j possessed greater anticancer potential for further evaluations.Keywords: synthesis, xanthone, derivatives, lung cancer cell, apoptosis
