Structure–activity relationships of resveratrol and derivatives in breast cancer cells

Resveratrol (RSV) is classified as a phytoestrogen due to its ability to interact with estrogen receptors (ERs). We assessed structure–activity relationships of RSV and the analogs 4,4'-dihydroxystilbene (4,4'-DHS), 3,5-dihydroxystilbene (3,5-DHS), 3,4'-dihydroxystilbene (3,4'-DHS), 4-hydroxystilbene (4-HS) using as model systems the ERa-positive and negative MCF7 and SkBr3 breast cancer cells, respectively. In binding assays and transfection experiments RSV and the analogs showed the following order of agonism for ERa: 3,4'-DHS > 4,4'-DHS > 4-HS > RSV, while 3,5-DHS did not elicit any ligand properties. Computational docking analysis and real-time PCR revealed for each analog a distinct ERa binding orientation and estrogen target gene expression profile. Interestingly, the aforementionedorder of ligand activity was confirmed in proliferation assays which also showed the lack of growth stimulation by 3,5-DHS. Our data suggest that subtle changes in the structure of the RSVderivatives examined may be responsible for the different ERa-mediated biological responses observed in estrogen-sensitive cancer cells.