Synthesis and biological evaluation of bis-chalcone conjugates containing lysine linker as potential anticancer agents

Eight bis-chalcone conjugates with lysine linker were synthesized by alkylation reaction and evaluated for the antiproliferative potential. All the newly synthesized derivatives were first screened against Liver cancer (MHCC-97H), Colorectal cancer (HCT116), and Gastric cancer (TMK1) using CCK-8 assay under the concentrations from 0 to 100 mu M, suggesting that gastric cancer cell TMK1 is more sensitive to these derivatives except 3d and 3f. Further, these compounds were tested in more gastric cancer-related cells including MKN45, AGS, IM95 and a normal gastric epithelial (GES1) cell line. Results indicated that the derivative 3a exhibited the most potent activity against TMK1 (IC50 = 22.29 mu M, near to the reference drug 5-FU) and AGS(IC50 = 22.14 mu M). In vivo anti-tumor study showed that compound 3a effectively inhibited tumor growth in TMK1-induced xenograft model without visible side effects. The mechanism of action on 3a on tumor growth inhibition was further investigated by RNA-Seq analysis in TMK1 cells, which indicates a positive regulation of apoptotic signaling pathway. Finally, cancer cell apoptosis after treated with 3a was confirmed with the expression of Annexin V, cleaved caspase 3 and Bax in TMK1 cells. Our results suggest that the bis-chalcone conjugate compound 3a is a promising tumor inhibitory agent for some gastric cancer.