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.