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.

Automated summary

Eight bis-chalcone conjugates with lysine linker were synthesized and evaluated for their antiproliferative potential. The derivatives showed good sensitivity against gastric cancer cells TMK1 and AGS, with compound 3a exhibiting the most potent activity. In vivo studies demonstrated that compound 3a effectively inhibited tumor growth in a xenograft model. The mechanism of action of 3a in tumor growth inhibition was further investigated, revealing a positive regulation of apoptotic signaling pathway.