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ChemMedChem. 2018 Jun 6;13(11):1115-1123. doi: 10.1002/cmdc.201800135. Epub 2018 Apr 23.

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

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Department of Chemistry, University of Bayreuth, Universitätsstraße 30, 95440, Bayreuth, Germany.
University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
Developmental Biology, University of Bayreuth, Universitätsstraße 30, 95440, Bayreuth, Germany.


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.


angiogenesis; anticancer agents; curcuminoids; halogenation; piperidone

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