TITLE:
Trisubstituted Hexahydroimidazo[1,2-α]Pyridine 6 (TIP-6) as a Small-Molecule Inhibitor of Bcl-2 for Inhibition of Proliferation in Hepatoma Cells
AUTHORS:
Wenchao Zhang, Yanlong Pan, Heng Zhou, Xiaofei Gao, Jizu Song, Yuexia Hua, Yuping Du, Jinbo Yang, Xinping Hui, Qin Wang
KEYWORDS:
TIP-6, Antiproliferative, Autophagy, Bcl-2, LC3, Docking
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.7 No.1,
January
4,
2019
ABSTRACT: Background: Cancer poses a serious threat to human health and survival, and
studies had been reported that imidazole or pyridine analogs play as an
anti-cancer agent in cancer treatment. Meanwhile, Autophagy plays a dual and
substantial role in maintaining cellular homeostasis in cancers, for it is
either initiated to rescue cancer cells under stress or executed to promote
autophagy cell death under certain circumstances. Objective: TIP-6 was designed
and synthesized (7-(4-methoxyphenyl)-5,8α-diphenyl-1,2,3,7,8, 8α-hexahyd-roimidazo[1,2-α]pyridine-6) for evaluation of its
biological effects on HepG2 cells and exploring the potential anti-cancer
effect. Methods and Results: Chemical synthesis results indicated that
the expected compound was obtained. The results of the MTT assay showed that
TIP-6 arrested the growth of HepG2 cells in G2/M phase in the cell cycle,
showing significant anti-proliferation effect. And analysis of morphological
changes and formation of acidic vesicular organelles showed that the autophagy
was induced but not apoptosis. The results were further validated by the enhanced
expression of LC3I/II, Beclin1and down-regulated expression of Bcl-2in western
blot analysis. In addition, the molecular docking predicted that TIP-6
preferentially binds to Bcl-2 and Bcl-xL in the active sites. Conclusion: Overall,
this study demonstrated that autophagy cell death was executed in HepG2 cells
which were induced by TIP-6.