Prenylflavonoids as Nonsteroidal Phytoestrogens and Related Structure–Activity Relationships

Abstract

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 an estrogen-screening assay. Cell-cycle analysis revealed that the stimulatory effects of these compounds toward cell proliferation were elicited at the G1–S checkpoint and could significantly increase the S-phase population 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 ((7α-[9-{4,4,5,5,5-pentafluoropentyl}sulfinyl]nonyl)estra-1,3,5(10)-triene-3,17β-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 prenylflavonoids, protein–ligand docking simulations were carried out by using the DS-MODELING software package. The binding affinity of each prenylflavonoid toward ERα was scored, and the receptor–ligand interaction was also analyzed to provide the simulation characteristics of virtual molecular recognition mechanisms.