Prenylflavonoids as nonsteroidal phytoestrogens and related structure-activity relationships

In the search for estrogen receptor (ER) modulators, a series of prenylflavonoids were found to be widely distributed amongst tonic herbal medicines and to possess estrogen-like activity in MCF-7/BOS cells, as evaluated by on estrogen-screening assay. Cell-cycle analysis revealed that the stimulatory effects of these I compounds toward cell proliferation were elicited at the G1-5 checkpoint and could significantly increase the S-phase popula of MCF-7 cells under hormone-free conditions. ER-responsive gene (PS2, PgR) and protein (PgR) expression was also detected; mRNA and protein -expression levels for PS2 and PgR were up-regulated by the compounds in a dose-dependent manner. These effects could be inhibited by the pure ER antagonist ICI 182,780 ((7 alpha-[9-[4,4,5,5,5-pentafluoropentyl]sulfinyl]nonyl)estra-1,3,5(10)-triene-3,17 beta-diol). It was therefore concluded that the estrogen-like effects of these prenylflavonoids were mediated primarily through ERs. Furthermore, to explore the structure-activity relationship based on the estrogen receptor and detailed molecular mechanisms among the prenylflovonoids, protein-ligand docking simulations were carried out by using the DS-MODELING softwore package. The binding affinity of each prenylflavonoid toward ERa was scored, and the receptor-ligand interaction was also analyzed to provide the simulation characteristics of virtual molecular recognition mechanisms.