Advertisement

Molecular aspects of phytoestrogen selective binding at estrogen receptors

      ABSTRACT

      Phytoestrogens are a diverse group of plant‐derived compounds that structurally or functionally mimic mammalian estrogens and show potential benefits for human health. An increase in phytoestrogen research over the past few decades has demonstrated the biological complexity of phytoestrogens, which belong to several different chemical classes and act through diverse mechanisms. Identification of the estrogen receptor β (ERβ) and research into various ligand classes has enabled elucidation of molecular aspects important in selective ER binding. This article explores the structural characteristics and significance of functional groups as they relate to phytoestrogen selectivity for ER binding. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:1879–1885, 2007

      Keywords

      To read this article in full you will need to make a payment
      APhA Member Login
      APhA Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • Cassidy A.
        Dietary phytoestrogens—anti‐cancer agents?.
        Br Nutr Found Bull. 1999; 24: 22-30
        • Adlercreutz H.
        Phyto‐oestrogens and cancer.
        Lancet Oncol. 2002; 3: 364-373
        • Morrissey C.
        • Watson R.W.
        Phytoestrogens and prostate cancer.
        Curr Drug Targets. 2003; 4: 231-241
        • Peeters P.H.
        • Keinan‐Boker L.
        • van der Schouw Y.T.
        • Grobbee D.E.
        Phytoestrogens and breast cancer risk. Review of the epidemiological evidence.
        Breast Cancer Res Treat. 2003; 77: 171-183
        • Murkies A.L.
        • Lombard C.
        • Strauss B.J.G.
        • Wilcox G.
        • Burger H.G.
        • Morton M.S.
        Dietary flour supplementation decreases post‐menopausal hot flushes: Effect of soy and wheat.
        Maturitas. 1995; 21: 189-195
        • Stephens F.O.
        The increased incidence of cancer of the pancreas: Is there a missing dietary factor? Can it be reversed?.
        Aust N Z J Surg. 1999; 69: 331-335
        • Mosselman S.
        • Polman J.
        • Dijkema R.
        ER beta: Identification and characterization of a novel human estrogen receptor.
        FEBS Lett. 1996; 392: 49-53
        • Kim S.
        • Wu J.Y.
        • Birzin E.T.
        • Frisch K.
        • Chan W.
        • Pai L.‐.Y.
        • Yang Y.T.
        • Mosley R.T.
        • Fitzgerald P.M.D.
        • Sharma N.
        • Dahllund J.
        • Thorsell A.‐.G.
        • DiNinno F.
        • Rohrer S.P.
        • Schaeffer J.M.
        • Hammond M.L.
        Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor modulators.
        J Med Chem. 2004; 47: 2171-2175
        • Mortensen D.S.
        • Rodriguez A.L.
        • Carlson K.E.
        • Sun J.
        • Katzenellenbogen B.S.
        • Katzenellenbogen J.A.
        Synthesis and biological evaluation of a novel series of furans: Ligands selective for estrogen receptor alpha.
        J Med Chem. 2001; 44: 3838-3848
        • Meyers M.J.
        • Sun J.
        • Carlson K.E.
        • Marriner G.A.
        • Katzenellenbogen B.S.
        • Katzenellenbogen J.A.
        Estrogen receptor‐ potency‐selective ligands: Structure–activity relationship studies of diarylpropionitriles and their acetylene and polar analogues.
        J Med Chem. 2001; 44: 4230-4251
        • Morito K.
        • Aomori T.
        • Hirose T.
        • Kinjo J.
        • Hasegawa J.
        • Ogawa S.
        • Inoue S.
        • Muramatsu M.
        • Masamune T.
        Interaction of phytoestrogens with estrogen receptors alpha and beta (II).
        Biol Pharm Bull. 2002; 25: 48-52
        • Anstead G.M.
        • Carlson K.E.
        • Katzenellenbogen J.A.
        The estradiol pharmacophore: Ligand structure‐estrogen receptor binding affinity relationships and a model for the receptor binding site.
        Steroids. 1997; 62: 268-303
        • Hu J.Y.
        • Aizawa T.
        Quantitative structure–activity relationships for estrogen receptor binding affinity of phenolic chemicals.
        Water Res. 2003; 37: 1213-1222
        • Brzozowski A.M.
        • Pike A.C.
        • Dauter Z.
        • Hubbard R.E.
        • Bonn T.
        • Engstrom O.
        • Ohman L.
        • Greene G.L.
        • Gustafsson J.A.
        • Carlquist M.
        Molecular basis of agonism and antagonism in the oestrogen receptor.
        Nature. 1997; 389: 753-758
        • Kuiper G.G.
        • Carlsson B.
        • Grandien K.
        • Enmark E.
        • Haggblad J.
        • Nilsson S.
        • Gustafsson J.A.
        Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta.
        Endocrinology. 1997; 138: 863-870
        • Mukherjee S.
        • Mukherjee A.
        • Saha A.
        QSAR modeling on binding affinity of diverse estrogenic flavonoids: Electronic, topological and spatial functions in quantitative approximation.
        J Mol Struct Theochem. 2005; 715: 85-90
        • Sun W.
        • Cama L.D.
        • Birzin E.T.
        • Warrier S.
        • Locco L.
        • Mosley R.
        • Hammond M.L.
        • Rohrer S.P.
        6H‐Benzo[c]chromen‐6‐one derivatives as selective ER‐beta agonists.
        Bioorg Med Chem Lett. 2006; 16: 1468-1472
        • Agatonovic‐Kustrin S.
        • Turner J.V.
        Artificial neural network modeling of phytoestrogen binding to estrogen receptors.
        Lett Drug Des Discov. 2006; 7: 436-442
        • Bickoff E.M.
        • Booth A.N.
        • Lyman R.L.
        • Livingston A.L.
        • Thompson C.R.
        • Deeds F.
        Coumestrol, a new estrogen isolated from forage crops.
        Science. 1957; 126: 969-970
        • Bakhchinian R.
        • Terrier F.
        • Kirkiacharian S.
        • Resche‐Rigon M.
        • Bouchoux F.
        • Cerede E.
        Synthesis and relative binding affinity to human steroid receptors of substituted 3‐aryloxycoumarins.
        Il Farmaco. 2003; 58: 1201-1207
        • Kirkiacharian S.
        • Lormier A.T.
        • Resche‐Rigon M.
        • Bouchoux F.
        • Cerede E.
        Synthesis and binding affinity of 3‐aryl‐7‐hydroxycoumarins to human alpha and beta estrogen receptors.
        Ann Pharm Fr. 2003; 61: 51-56
        • Kirkiacharian S.
        • Lormier A.T.
        • Chidiack H.
        • Bouchoux F.
        • Cérède E.
        Synthesis and binding affinity to human alpha and beta estrogen receptors of various 7‐hydroxycoumarins substituted at 4‐ and 3,4‐positions.
        Il Farmaco. 2004; 59: 981-986
        • Tong W.
        • Perkins R.
        • Xing L.
        • Welsh W.J.
        • Sheehan D.M.
        QSAR models for binding of estrogenic compounds to estrogen receptor alpha and beta subtypes.
        Endocrinology. 1997; 138: 4022-4025
        • Larrea F.
        • Garcia‐Becerra R.
        • Lemus A.E.
        • Garcia G.A.
        • Perez‐Palacios G.
        • Jackson K.J.
        • Coleman K.M.
        • Dace R.
        • Smith C.L.
        • Cooney A.J.
        A‐ring reduced metabolites of 19‐nor synthetic progestins as subtype selective agonists for ER alpha.
        Endocrinology. 2001; 142: 3791-3799
        • Fink B.E.
        • Mortensen D.S.
        • Stauffer S.R.
        • Aron Z.D.
        • Katzenellenbogen J.A.
        Novel structural templates for estrogen‐receptor ligands and prospects for combinatorial synthesis of estrogens.
        Chem Biol. 1999; 6: 205-209
        • Kuiper G.G.
        • Lemmen J.G.
        • Carlsson B.
        • Corton J.C.
        • Safe S.H.
        • van der Saag P.T.
        • van der Burg B.
        • Gustafsson J.A.
        Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.
        Endocrinology. 1998; 139: 4252-4263
        • Sun J.
        • Meyers M.J.
        • Fink B.E.
        • Rajendran R.
        • Katzenellenbogen J.A.
        • Katzenellenbogen B.S.
        Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor‐alpha or estrogen receptor‐beta.
        Endocrinology. 1999; 140: 800-804
        • Stauffer S.R.
        • Huang Y.
        • Coletta C.J.
        • Tedesco R.
        • Katzenellenbogen J.A.
        Estrogen pyrazoles: Defining the pyrazole core structure and the orientation of substituents in the ligand binding pocket of the estrogen receptor.
        Bioorg Med Chem. 2001; 9: 141-150
        • Kousteni S.
        • Bellido T.
        • Plotkin L.I.
        • O'Brien C.A.
        • Bodenner D.L.
        • Han L.
        • Han K.
        • DiGregorio G.B.
        • Katzenellenbogen J.A.
        • Katzenellenbogen B.S.
        • Roberson P.K.
        • Weinstein R.S.
        • Jilka R.L.
        • Manolagas S.C.
        Nongenotropic, sex‐nonspecific signaling through the estrogen or androgen receptors: Dissociation from transcriptional activity.
        Cell. 2001; 104: 719-730
        • Wilkening R.R.
        • Ratcliffe R.W.
        • Tynebor E.C.
        • Wildonger K.J.
        • Fried A.K.
        • Hammond M.L.
        • Mosley R.T.
        • Fitzgerald P.M.
        • Sharma N.
        • McKeever B.M.
        • Nilsson S.
        • Carlquist M.
        • Thorsell A.
        • Locco L.
        • Katz R.
        • Frisch K.
        • Birzin E.T.
        • Wilkinson H.A.
        • Mitra S.
        • Cai S.
        • Hayes E.C.
        • Schaeffer J.M.
        • Rohrer S.P.
        The discovery of tetrahydrofluorenones as a new class of estrogen receptor beta‐subtype selective ligands.
        Bioorg Med Chem Lett. 2006; 16: 3489-3494
        • Meyers M.J.
        • Sun J.
        • Carlson K.E.
        • Katzenellenbogen B.S.
        • Katzenellenbogen J.A.
        Estrogen receptor subtype‐selective ligands: Asymmetric synthesis and biological evaluation of cis‐ and trans‐5,11‐dialkyl‐5,6,11,12‐tetrahydrochrysenes.
        J Med Chem. 1999; 42: 2456-2468
        • Shiau A.K.
        • Barstad D.
        • Radek J.L.
        • Meyers M.J.
        • Nettles K.W.
        • Katzenellenbogen B.S.
        • Katzenellenbogen J.A.
        • Agard D.A.
        • Greene G.L.
        Structural characterization of a subtype‐selective ligand reveals a novel mode of estrogen receptor antagonism.
        Nat Struct Biol. 2002; 9: 360-364
        • Nichols M.
        • Rientjes J.M.J.
        • Stewart A.F.
        Different positioning of the ligand‐binding domain helix 12 and the F domain of the estrogen receptor accounts for functional differences between agonists and antagonists.
        EMBO J. 1998; 17: 765-773
        • Vu A.T.
        • Cohn S.T.
        • Manas E.S.
        • Harris H.A.
        • Mewshaw R.E.
        ERbeta ligands. Part 4. Synthesis and structure–activity relationships of a series of 2‐phenylquinoline derivatives.
        Bioorg Med Chem Lett. 2005; 15: 4520-4525
        • Minutolo F.
        • Antonello M.
        • Bertini S.
        • Ortore G.
        • Placanica G.
        • Rapposelli S.
        • Sheng S.
        • Carlson K.E.
        • Katzenellenbogen B.S.
        • Katzenellenbogen J.A.
        • Macchia M.
        Novel estrogen receptor ligands based on an anthranylaldoxime structure: Role of the phenol‐type pseudocycle in the binding process.
        J Med Chem. 2003; 46: 4032-4042
        • Minutolo F.
        • Antonello M.
        • Bertini S.
        • Rapposelli S.
        • Rossello A.
        • Sheng S.
        • Carlson K.E.
        • Katzenellenbogen J.A.
        • Macchia M.
        Synthesis, binding affinity, and transcriptional activity of hydroxy‐ and methoxy‐substituted 3,4‐diarylsalicylaldoximes on estrogen receptors alpha and beta.
        Bioorg Med Chem. 2003; 11: 1247-1257
        • Minutolo F.
        • Bertini S.
        • Martinelli A.
        • Ortore G.
        • Placanica G.
        • Prota G.
        • Rapposelli S.
        • Tuccinardi T.
        • Sheng S.
        • Carlson K.E.
        • Katzenellenbogen B.S.
        • Katzenellenbogen J.A.
        • Macchia M.
        Salicylaldoximes and anthranylaldoximes as alternative to phenol‐based estrogen receptor ligands.
        Arkivoc. 2006; 8: 83-94