Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells

Purpose To study anticancer activities of 68 plant polyphenols with different backbone structures and various substitutions and to analyze the structure - activity relationships. Methods Antiproliferative activity of 68 plant polyphenols on human liver cancer cells were screened by the 3-[ 4,5- dimethylthiazol-2yl]- 2,5- diphenyltetrazolium bromide method. Structure - activity relationships were analyzed by comparison of their activities with selected structures. Cell cycle progression was assayed by flow cytometry analysis and apoptosis was analyzed by DNA fragment assay. Results Based on their backbone structures, 68 polyphenols were sub-classed to flavonoids (chalcones, flavanones, flavones and isoflavones), chromones and coumarins. The order of their potency to suppress the human liver cancer cells is chalcones > flavones > chromones > isoflavones > flavanones > coumarins. Chalcones comprise the most potent group with IC50 values ranging from 21.69 to 197 mu M. Top nine most potent chalcones in the group have hydroxylation at 2 '-carbon position in B-ring. Flavones ranked second in their potencies. Quercetin, 4-hydroxyflavone and luteolin are three hydroxyflavones with highest potencies in this group. Their IC50 values are 30.81, 39.29 and 71.17 mu M, respectively. Chromones, isoflavones, flavanones and coumarins showed much lower potencies when compared to the first two groups with IC50 ranges of 61 to > 400, 131 to > 400, 138 to > 400 and 360.85 to > 400 mu M, respectively. In mechanistic studies, the most potent chalcone, 2,2 '-dihydroxychalcone could induce G2/M arrest and then apoptosis of the cancer cells. Conclusions An analysis of structure -activity relationship showed that following structures are required for their inhibitory potencies on human liver cancer cells: (1) of the six sub-classes of the polyphenols tested, the unique backbone structure of chalcones with a open C-ring; (2) within the chalcone group, hydroxyl substitution at 2 '-carbon of B-ring; (3) hydroxyl substitution at 3 '-carbon in B-ring of Xavones. However, some other structures were found to decrease their potencies: e. g. substitutions by sugar moieties in Xavones. These data are valuable for design and modification of new polyphenols, which could be potential antiproliferative agents of cancer cells.