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 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 ((7alpha-[9-{4,4,5,5,5-pentafluoropentyl}sulfinyl]nonyl)estra-1,3,5(10)-triene-3,17beta-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 ERalpha was scored, and the receptor-ligand interaction was also analyzed to provide the simulation characteristics of virtual molecular recognition mechanisms.
Wang
Zhi-qiang
ZQ
Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310031, China.
Weber
Nadine
N
Lou
Yi-jia
YJ
Proksch
Peter
P
D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D017931:DNA Primers; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D048789:Phytoestrogens / Q000737:chemistry / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
D017931:DNA Primers; D005419:Flavonoids; D048789:Phytoestrogens