Halogenated Bis(methoxybenzylidene)-4-piperidone Curcuminoids with Improved Anticancer Activity

A series of readily available curcuminoids with a halogenated bis(4-methoxy/4,5-dimethoxybenzylidene)-4-piperidone structure were prepared and analyzed for their cytotoxic impact on eight human cancer cell lines of five different entities. The known 3,4,5-trimethoxybenzylidene curcuminoid 2 a and the new bis-(3-bromophenyl) and bis-(3,5-dibromophenyl) derivatives 3 c and 3 d proved to be more strongly antiproliferative than the known curcuminoid EF24 against six of these cell lines. Compounds 2 a and 3 c caused a distinct increase of reactive oxygen species, which eventually elicited apoptosis in 518A2 melanoma cells. Compound 2 a arrested 518A2 melanoma cells in G₁ phase of the cell cycle and had no effect on the expression of pro-metastatic matrix metalloproteinases MMP-2 and MMP-9, whereas 3 c led to an accumulation of 518A2 cells in the G₂ /M phase and to a downregulation of MMP-2 expression. In addition, treatment with 2 a and 3 c resulted in significant inhibition of colony formation in HCT116 cells. Both 2 a and 3 c showed antiangiogenic activity, for example, by inhibiting the formation of sub-intestinal veins (SIV) in zebrafish embryos. Compound 3 c was also well tolerated by mice and inhibited the growth of HCT116 colon cancer xenografts.