Design, synthesis and anti-gastric cancer activity of stable Bisamide curcumin analogues

Curcumin, as a natural product, exhibits notable antitumor activity; however, its further development is limited by poor stability and unfavorable pharmacokinetic properties. To enhance the stability and pharmacological activity of curcumin, a series of stable bisamide curcumin analogs were designed and synthesized through amide bond introduction. Several compounds demonstrated high efficacy in suppressing the proliferation of gastric cancer cells in vitro. The quantitative structure-activity relationship models (QSAR) of compounds were established by random forest algorithm and R² in two gastric cancer cells were greater than 0.9. The most promising active compound KB-15 significantly inhibits proliferation, cell colony formation, and migration in both AGS and BGC-823 cells in a concentration dependent manner. Additionally, KB-15 was found to induce cell cycle arrest and promote apoptosis. In a BGC-823 xenograft mouse model, KB-15 demonstrated robust inhibitory activity on gastric cancer growth in vivo. Mechanistic studies revealed that KB-15 exerts its antitumor effects by inhibiting STAT3 phosphorylation and downregulating HO-1 expression. Compared with curcumin, KB-15 demonstrated significantly enhanced stability and improved pharmacokinetic parameters. In summary, this study presents a promising series of bisamide curcumin analogs, with KB-15 being a potential candidate for further development as an antitumor drug.