Wei Gao,Xiaoju Hua,Shengliang Liao,Zhikai Xiahou,Haikuan Yang,Lifang Hu,Yunyang Chi
Graphical Compound 3h has been found to show inhibitory effects on the survival of HepG2 liver cancer cells.The results show that 3h induces cell-cycle arrest in the S phase. Additionally, 3h exerts a strong pro-apoptotic effect. Specifically, compound 3h reduces the phosphorylation of PI3K, AKT, and ERK, thereby inhibiting both the MAPK/ERK and PI3K/AKT signaling pathways. 2H-pyran compound 1 synthesized from 6-methylpyridine-2,4-diol and citral, has been used for Cu-catalyzed N -arylation with a range of arylboric acids to obtain arylated pyranopyridine core structure derivatives (yield up to 77 %). Among them, compound 3 h exhibited a much better inhibitory effect on HepG2 liver cancer cells compared to citral, and the IC 50 value was 5.3 μM following exposure with the newly synthesized derivatives (herein named 3 h for short in this paper), which was lower than that of the cisplatin (6.5 μM). Meanwhile, the cell-cycle arrest of HepG2 cells occurred in the S phase, and the apoptosis of HepG2 cells was significantly increased with increasing drug concentration. In addition, real-time fluorescence quantification PCR and Western blotting experiments showed that the expression of apoptotic protein BAX was increased, while the expression of anti-apoptotic protein BCL2 was inhibited in a dose-dependent fashion. The results of these experiments indicated that apoptosis was promoted in HepG2 cells via apoptotic signaling pathway activated by 3 h . Furthermore, 3 h effectively decreased the phosphorylation levels of PI3 K, ATK and ERK, resulting in the inhibitions of MAPK/ERK and PI3 K/ATK signaling pathways. Briefly, 3 h has been found to show inhibitory effects on the survival of HepG2 liver cancer cells and may be used as anti-cancer drug in the future.
Meng-qiu Song,Wei Min,Jing Wang,Xin-Xin Si,Xiu-Jun Wang,Yu-Wei Liu,Da-Hua Shi
Twelve carbazole-coumarin hybrids were synthesized and biologically evaluated as dual binding site acetylcholinesterase inhibitors. The structures of the carbazole-coumarin hybrids were confirmed by IR, NMR, HRMS and single-crystal X-ray diffraction studies. The compound 3j had the crystal system of triclinic and the space group of P-1. The cholinesterase inhibitory activity of synthesized compounds was measured using colorimetric Ellman's method. Compound 3h exhibited good acetylcholinesterase (AChE) inhibitory activity (IC 50 value of 6.72 μ M) and a high selectivity over butyrylcholinesterase (BuChE). Compound 3k showed the best BuChE inhibitory activity with the IC 50 of 0.50 μM. The SAR studies revealed that the linker length played a crucial role in determining AChE inhibitory activity and the structure of the coumarin moieties affected the BuChE-inhibition activities of the hybrids. Molecular docking study of compound 3h indicated that it interacts with the crucial amino acids present at the catalytic active site and peripheral anionic site of AChE. Compound 3h would be a promising drug candidate to treat AD as a selective and dual binding site inhibitor of AChE.
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