Prenylflavonoids as nonsteroidal phytoestrogens and related structure-activity relationships

被引:25
作者
Wang, Zhi-qiang
Weber, Nadine
Lou, Yi-jia
Proksch, Peter
机构
[1] Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou
关键词
D O I
10.1002/cmdc.200500089
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
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收藏
页码:482 / 488
页数:7
相关论文
共 27 条
[1]   Phytoestrogens, cancer and coronary heart disease [J].
Adlercreutz, H ;
Heinonen, SM ;
Penalvo-Garcia, J .
BIOFACTORS, 2004, 22 (1-4) :229-236
[2]   The estradiol pharmacophore: Ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site [J].
Anstead, GM ;
Carlson, KE ;
Katzenellenbogen, JA .
STEROIDS, 1997, 62 (03) :268-303
[3]   CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS [J].
BROOKS, BR ;
BRUCCOLERI, RE ;
OLAFSON, BD ;
STATES, DJ ;
SWAMINATHAN, S ;
KARPLUS, M .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 1983, 4 (02) :187-217
[4]   Molecular basis of agonism and antagonism in the oestrogen receptor [J].
Brzozowski, AM ;
Pike, ACW ;
Dauter, Z ;
Hubbard, RE ;
Bonn, T ;
Engstrom, O ;
Ohman, L ;
Greene, GL ;
Gustafsson, JA ;
Carlquist, M .
NATURE, 1997, 389 (6652) :753-758
[5]  
Cos P, 2003, PLANTA MED, V69, P589, DOI 10.1055/s-2003-41122
[6]   Estrogen receptor null mice: What have we learned and where will they lead us? [J].
Couse, JF ;
Korach, KS .
ENDOCRINE REVIEWS, 1999, 20 (03) :358-417
[7]   Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells [J].
Doisneau-Sixou, SF ;
Sergio, CM ;
Carroll, JS ;
Hui, R ;
Musgrove, EA ;
Sutherland, RL .
ENDOCRINE-RELATED CANCER, 2003, 10 (02) :179-186
[8]   Estrogens and cell-cycle regulation in breast cancer [J].
Foster, JS ;
Henley, DC ;
Ahamed, S ;
Wimalasena, J .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2001, 12 (07) :320-327
[9]   Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: Insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype [J].
Frasor, J ;
Danes, JM ;
Komm, B ;
Chang, KCN ;
Lyttle, CR ;
Katzenellenbogen, BS .
ENDOCRINOLOGY, 2003, 144 (10) :4562-4574
[10]   The multifaceted mechanisms of estradiol and estrogen receptor signaling [J].
Hall, JM ;
Couse, JF ;
Korach, KS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (40) :36869-36872