High Anti-cancer Activity, Low Animal Toxicity, and Structure Activity Relationships of Curcumin Analogs

Background: Inhibition of cancer cell growth and low in vivo toxicity are two important criteria for the development of anti-cancer drugs. Curcumin is a promising candidate for developing novel anti-cancer drug analogs. The research group designed the 3,5-bis-(3,4,5- trimethoxybenzylidene)-1-methyl-piperidin-4-one analog of curcumin that significantly inhibited the growth of esophageal cancer cells in vivo. In this study, 81 curcumin analogs were synthesized, analyzed both in vitro and in vivo, and their structure activity relationships (SARs) were determined. Methods: Based on the parent structure of curcumin, 81 analogs of 3,5-bis(substitutedbenzylidene)- piperidin-4-one compounds were designed and synthesized. Their anti-cancer activity in the human cancer cell lines was evaluated using the MTT assay, and in vivo toxicity was evaluated in mice. The SARs of selected compounds were analyzed. Results and Discussion: Among the designed curcumin analogs, 61 compounds exerted anti-cancer effects higher than the parent compound in vitro; 23 compounds inhibited cell growth in the human cancer cell line at low concentrations (IC50 values below 1 μM). The acute toxicity of curcumin analogs was tested in mice; 13 compounds were selected, which did not show any obvious toxicity at doses as high as 25.0 mg/kg. The SARs of these shortlisted curcumin analogs were determined. Conclusion: Twenty-three curcumin analogs exhibiting promising in vitro anti-cancer activity and low in vivo toxicity were designed. SAR analysis indicated the optimal functional groups in the molecule required for anti-cancer activity. This study not only suggested a useful strategy to design curcumin analogs for the development of anti-cancer drugs, but also revealed a group of curcumin analogs which could be further explored.