Trisubstituted Hexahydroimidazo[1,2-<i>α</i>]Pyridine 6 (TIP-6) as a Small-Molecule Inhibitor of Bcl-2 for Inhibition of Proliferation in Hepatoma Cells

Background: Cancer poses a serious threat to human health and survival, andstudies had been reported that imidazole or pyridine analogs play as ananti-cancer agent in cancer treatment. Meanwhile, Autophagy plays a dual andsubstantial role in maintaining cellular homeostasis in cancers, for it iseither initiated to rescue cancer cells under stress or executed to promoteautophagy cell death under certain circumstances. Objective: TIP-6 was designedand synthesized (7-(4-methoxyphenyl)-5,8α-diphenyl-1,2,3,7,8, 8α-hexahyd-roimidazo[1,2-α]pyridine-6) for evaluation of itsbiological effects on HepG2 cells and exploring the potential anti-cancereffect. Methods and Results: Chemical synthesis results indicated thatthe expected compound was obtained. The results of the MTT assay showed thatTIP-6 arrested the growth of HepG2 cells in G2/M phase in the cell cycle,showing significant anti-proliferation effect. And analysis of morphologicalchanges and formation of acidic vesicular organelles showed that the autophagywas induced but not apoptosis. The results were further validated by the enhancedexpression of LC3I/II, Beclin1and down-regulated expression of Bcl-2in westernblot analysis. In addition, the molecular docking predicted that TIP-6preferentially binds to Bcl-2 and Bcl-xL in the active sites. Conclusion: Overall,this study demonstrated that autophagy cell death was executed in HepG2 cellswhich were induced by TIP-6.