Abstract
Curcumin possesses a variety of pharmacological properties, particularly anticancer activity. However, its clinical utility is limited by its poor water solubility and low bioavailability. To alleviate the problems, our previous research demonstrated that mono-carbonyl curcumin easters can be employed for the development of novel anticancer agents. In this study, further structural optimization was performed and a series of novel amino acid conjugates of mono-carbonyl curcumin H1-H6 were designed, synthesized, and evaluated by in vitro and in vivo studies. Compound H1 was found as the most potent derivative (IC(50) = 8.66 µM) compared to curcumin (IC(50) = 36.19 µM) by anti-proliferation assay. Subsequently, wound healing, transwell, JC-1 staining, the HepG2 cell xenograft model and H&E staining experiments were performed, and it was found that compound H1 was more effective than curcumin in inhibiting tumor growth. The results of transcriptome sequence, bioinformatics analysis, molecular docking, and western blotting suggested that compound H1 could inhibit cell proliferation and induce apoptosis through the AKT/FOXO1 pathway. Hence, H1 is a promising lead compound with the potential to be developed as a chemotherapy agent for hepatocellular carcinoma.