Title:Design, Synthesis and Bioactivity Evaluation of Novel Chalcone Derivatives
Possessing Tryptophan Moiety with Dual Activities of Anti-Cancer and Partially
Restoring the Proliferation of Normal Kidney Cells Pre-Treated with Cisplatin
Volume: 22
Issue: 10
Author(s): Meng He, Mingjun Yu, Chao Li, Xiaoming Meng, Jiamin Su, Yuting Zhu and Risheng Yao*
Affiliation:
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
Keywords:
Chalcones, L-tryptophan, anti-cancer, colchicine, nephrotoxicity, HGC-27 cells, HK-2 cells.
Abstract:
Background: Chalcone is a broad-spectrum natural product with anti-cancer and anti-inflammatory activities.
However, low potency, low selectivity, and serious side effects limit its druggability. L-Tryptophan is an essential
precursor molecule of an anti-cancer active substance. Also, the indole moiety inhibits the proliferation of tumor cells
by binding to colchicine sites. A decrease in kidney cell activity caused by kidney inflammation is the primary side
effect of cancer therapy.
Objective: The purpose of this work was to design, synthesize, and perform bioactivity evaluation of novel chalcone
derivatives possessing tryptophan moiety with dual activities of anti-cancer and partially restoring the proliferation of
normal kidney cells pre-treated with cisplatin.
Methods: A series of novel chalcone derivatives possessing tryptophan moiety (5a-5g, 6a-6o) were designed, synthesized,
and evaluated for anti-cancer activity against four cancer cell lines (gastric (HGC-27), colon (HCT-116), prostate
(PC-3), and lung (A549)), and a human normal cell line (gastric mucosal epithelial (GES-1)). The activity of restoring
the proliferation of normal kidney cells pre-treated with cisplatin was evaluated by MTT assay. Cell cycle, apoptosis,
and apoptosis proteins (Bax and Bcl-2) were used to evaluate the anti-cancer mechanism of the most potent compound.
Moreover, a docking study was performed to explain the high anti-cancer activity of 6n. The expressions of TNF-α, IL-
6, and MCP-1 were detected by ELISA.
Results: Most of the compounds exhibited high anti-cancer activity against the HGC-27 cell line and exhibited low
toxicity against the normal cell line. Based on three rounds of a structure optimization, 6n was discovered as the most
potent compound against HGC-27 cells with an IC50 value of 2.02 μM and an SI value of 28.47. Further studies
demonstrated that 6n could induce cell cycle arrest at the G2/M phase and the apoptosis of the HGC-27 cell line by
reducing the expression of Bcl-2 and improving the expression level of Bax. Molecular docking result displayed 6n
bound to the colchicine site. At the same time, 6n also exhibited moderate activity of restoring the proliferation of
normal kidney cells pre-treated with cisplatin by reducing the expression of inflammatory substances.
Conclusion: Our findings collectively suggested that 6n should be further studied as a potential anti-cancer agent that
could partially restore the proliferation of normal kidney cells pre-treated with cisplatin in gastric cancer patients by an
anti-inflammatory pathway.