Identification of xenoestrogens in food additives by an integrated in silico and in vitro approach

Chemical Research in Toxicology

Volumn 22, Issue 1, 2009, Pages 52-63

  Amadasi, Alessio ^a   Mozzarelli, Andrea ^a,b   Meda, Clara ^c   Maggi, Adriana ^c   Cozzini, Pietro ^b,d  

^a Department of Biochemistry and Molecular Biology ^*

^b UNIVERSITY OF PARMA   (Italy)

^c National Institute for Biostructures and Biosystems   (Italy)

^d UNIVERSITY OF MILAN   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ESTROGEN DERIVATIVE; ESTROGEN RECEPTOR ALPHA; FOOD ADDITIVE; GALLIC ACID PROPYL ESTER; HEXYLRESORCINOL; LIGAND; SILICON; UNCLASSIFIED DRUG; XENOESTROGEN;

ARTICLE; BINDING AFFINITY; BINDING SITE; ESTROGEN ACTIVITY; FILTER; FOOD INTAKE; HUMAN; HUMAN CELL; IN VITRO STUDY; PREDICTION; PROTEIN ANALYSIS; PROTEIN STRUCTURE; TRANSACTIVATION; WORLD HEALTH ORGANIZATION;

ANIMALS; CELL LINE; DATABASES, FACTUAL; ESTROGEN RECEPTOR ALPHA; ESTROGENS; FOOD ADDITIVES; LIGANDS; MICE; PROPYL GALLATE; PROTEIN STRUCTURE, TERTIARY; STRUCTURE-ACTIVITY RELATIONSHIP; XENOBIOTICS;

EID: 61849169468     PISSN: 0893228X     EISSN: 15205010     Source Type: Journal    
DOI: 10.1021/tx800048m     Document Type: Article

References (103)

1. Dahlman-Wright, K., Cavailles, V., Fuqua, S. A., Jordan, V. C., Katzenellenbogen, J. A., Korach, K. S., Maggi, A., Muramatsu, M., Parker, M. G., and Gustafsson, J. A. (2006) International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol. Rev. 58, 773-781.
2. Pozzi, S., Benedusi, V., Maggi, A., and Vegeto, E. (2006) Estrogen action in neuroprotection and brain inflammation. Ann. N. Y. Acad. Sci. 1089, 302-323.
3. Gustafsson, J. A. (1999) Estrogen receptor beta-A new dimension in estrogen mechanism of action. J. Endocrinol. 163, 379-383.
4. Osborne, C. K., Zhao, H., and Fuqua, S. A. (2000) Selective estrogen receptor modulators: Structure, function, and clinical use. J. Clin. Oncol. 18, 3172-3186.
5. Heldring, N., Pike, A., Andersson, S., Matthews, J., Cheng, G., Hartman, J., Tujague, M., Strom, A., Treuter, E., Warner, M., and Gustafsson, J. A. (2007) Estrogen receptors: How do they signal and what are their targets. Physiol. Rev. 87, 905-931.
6. Blair, R. M., Fang, H., Branham, W. S., Hass, B. S., Dial, S. L., Moland, C. L., Tong, W., Shi, L., Perkins, R., and Sheehan, D. M. (2000) The estrogen receptor relative binding affinities of 188 natural and xenochemicals: Structural diversity of ligands. Toxicol. Sci. 54, 138-153.
7. Fang, H., Tong, W., Shi, L. M., Blair, R., Perkins, R., Branham, W., Hass, B. S., Xie, Q., Dial, S. L., Moland, C. L., and Sheehan, D. M.
8. (2001) Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens. Chem. Res. Toxicol. 14, 280-294.
9. Mueller, S. O. (2004) Xenoestrogens: Mechanisms of action and detection methods. Anal. Bioanal. Chem. 378, 582-587.
10. Gantchev, T. G., Ali, H., and van Lier, J. E. (1994) Quantitative structure-activity relationships/comparative molecular field analysis (QSAR/CoMFA) for receptor-binding properties of halogenated estradiol derivatives. J. Med. Chem. 37, 4164-4176.
11. Tong, W., Perkins, R., Xing, L., Welsh, W. J., and Sheehan, D. M. (1997) QSAR models for binding of estrogenic compounds to estrogen receptor alpha and beta subtypes. Endocrinology 138, 4022-4025.
12. Oostenbrink, B. C., Pitera, J. W., van Lipzig, M. M., Meerman, J. H., and van Gunsteren, W. F. (2000) Simulations of the estrogen receptor ligand-binding domain: Affinity of natural ligands and xenoestrogens. J. Med. Chem. 43, 4594-4605.
13. van Lipzig, M. M., ter Laak, A. M., Jongejan, A., Vermeulen, N. P., Wamelink, M., Geerke, D., and Meerman, J. H. (2004) Prediction of ligand binding affinity and orientation of xenoestrogens to the estrogen receptor by molecular dynamics simulations and the linear interaction energy method. J. Med. Chem. 47, 1018-1030.
14. Brzozowski, A. M., Pike, A. C, Dauter, Z., Hubbard, R. E., Bonn, T., Engstrom, O., Ohman, L., Greene, G. L., Gustafsson, J. A., and Carlquist, M. (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389, 753-758.
15. Shiau, A. K., Barstad, D., Loria, P. M., Cheng, L., Kushner, P. J., Agard, D. A., and Greene, G. L. (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95, 927-937.
16. Cozzini, P., and Dottorini, T. (2004) Is it possible docking and scoring new ligands with few experimental data? Preliminary results on estrogen receptor as a case study. Eur. J. Med. Chem. 39, 601-609.
17. Sivanesan, D., Rajnarayanan, R. V., Doherty, J., and Pattabiraman, N. (2005) In-silico screening using flexible ligand binding pockets: A molecular dynamics-based approach. J. Comput.-Aided Mol. Des. 19, 213-228.
18. Sherman, W., Day, T., Jacobson, M. P., Friesner, R. A., and Farid, R. (2006) Novel procedure for modeling ligand/receptor induced fit effects. J. Med. Chem. 49, 534-553.
19. Erickson, J. A., Jalaie, M., Robertson, D. H., Lewis, R. A., and Vieth, M. (2004) Lessons in molecular recognition: The effects of ligand and protein flexibility on molecular docking accuracy. J. Med. Chem. 47, 45-55.
20. Murray, C. W., Baxter, C. A., and Frenkel, A. D. (1999) The sensitivity of the results of molecular docking to induced fit effects: Application to thrombin, thermolysin and neuraminidase. J. Comput.-Aided Mol. Des. 13, 547-562.
21. Birch, L., Murray, C. W., Hartshorn, M. J., Tickle, I. J., and Verdonk, M. L. (2002) Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase. J. Comput.-Aided Mol. Des. 16, 855-869.
22. Carlson, H. A. (2002) Protein flexibility and drug design: how to hit a moving target. Curr. Opin. Chem. Biol. 6, 447-452.
23. Carlson, H. A., and McCammon, J. A. (2000) Accommodating protein flexibility in computational drug design. Mol. Pharmacol. 57, 213-218.
24. Teague, S. J. (2003) Implications of protein flexibility for drug discovery. Nat. Rev. Drug Discovery 2, 527-541.
25. Alonso, H., Bliznyuk, A. A., and Gready, J. E. (2006) Combining docking and molecular dynamic simulations in drug design. Med. Res. Rev. 26, 531-568.
26. Jiang, F., and Kim, S. H. (1991) "Soft docking": Matching of molecular surface cubes. J. Mol. Biol. 219, 79-102.
27. Leach, A. R. (1994) Ligand docking to proteins with discrete side-chain flexibility. J. Mol. Biol. 235, 345-356.
28. Schaffer, L., and Verkhivker, G. M. (1998) Predicting structural effects in HIV-1 protease mutant complexes with flexible ligand docking and protein side-chain optimization. Proteins 33, 295-310.
29. Moitessier, N., Therrien, E., and Hanessian, S. (2006) A method for induced-fit docking, scoring, and ranking of flexible ligands. Application to peptidic and pseudopeptidic beta-secretase (BACE 1) inhibitors. J. Med. Chem. 49, 5885-5894.
30. Claussen, H., Buning, C., Rarey, M., and Lengauer, T. (2001) FlexE: Efficient molecular docking considering protein structure variations. J. Mol. Biol. 308, 377-395.
31. Osterberg, F., Morris, G. M., Sanner, M. F., Olson, A. J., and Goodsell, D. S. (2002) Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins 46, 34-40.
32. Huang, S. Y., and Zou, X. (2007) Efficient molecular docking of NMR structures: Application to HIV-1 protease. Protein Sci. 16, 43-51.
33. Huang, S. Y., and Zou, X. (2007) Ensemble docking of multiple protein structures: Considering protein structural variations in molecular docking. Proteins 66, 399-421.
34. Knegtel, R. M., Kuntz, I. D., and Oshiro, C. M. (1997) Molecular docking to ensembles of protein structures. J. Mol. Biol. 266, 424-440.
35. Broughton, H. B. (2000) A method for including protein flexibility in protein-ligand docking: improving tools for database mining and virtual screening. J. Mol. Graphics Modell. 18, 247-257, 302-244.
36. Carlson, H. A., Masukawa, K. M., Rubins, K., Bushman, F. D., Jorgensen, W. L., Lins, R. D., Briggs, J. M., and McCammon, J. A. (2000) Developing a dynamic pharmacophore model for HIV-1 integrase. J. Med. Chem. 43, 2100-2114.
37. Zavodszky, M. I., Lei, M., Thorpe, M. F., Day, A. R., and Kuhn, L. A. (2004) Modeling correlated main-chain motions in proteins for flexible molecular recognition. Proteins 57, 243-261.
38. Cavasotto, C. N., Kovacs, J. A., and Abagyan, R. A. (2005) Representing receptor flexibility in ligand docking through relevant normal modes. J. Am. Chem. Soc. 127, 9632-9640.
39. Jones, G., Willett, P., Glen, R. C., Leach, A. R., and Taylor, R. (1997) Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol. 267, 727-748.
40. Kellogg, G. E., and Abraham, D. J. (2000) Hydrophobicity: is LogP(o/w) more than the sum of its parts? Eur. J. Med. Chem. 35, 651-661.
41. Kellogg, G. E., Burnett, J. C., and Abraham, D. J. (2001) Very empirical treatment of solvation and entropy: A force field derived from log Po/w. J. Comput.-Aided Mol. Des. 15, 381-393.
42. Amadasi, A., Spyrakis, F., Cozzini, P., Abraham, D. J., Kellogg, G. E., and Mozzarelli, A. (2006) Mapping the energetics of water-protein and water-ligand interactions with the "natural" HINT forcefield: Predictive tools for characterizing the roles of water in biomolecules. J. Mol. Biol. 358, 289-309.
43. Cozzini, P., Fornabaio, M., Marabotti, A., Abraham, D. J., Kellogg, G. E., and Mozzarelli, A. (2002) Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 1. Models without explicit constrained water. J. Med. Chem. 45, 2469-2483.
44. Cozzini, P., Fornabaio, M., Marabotti, A., Abraham, D. J., Kellogg, G. E., and Mozzarelli, A. (2004) Free energy of ligand binding to protein: evaluation of the contribution of water molecules by computational methods. Curr. Med. Chem. 11, 3093-3118.
45. Fornabaio, M., Spyrakis, F., Mozzarelli, A., Cozzini, P., Abraham, D. J., and Kellogg, G. E. (2004) Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes. J. Med. Chem. 47, 4507-4516.
46. Spyrakis, F., Amadasi, A., Fornabaio, M., Abraham, D. J., Mozzarelli, A., Kellogg, G. E., and Cozzini, P. (2007) The consequences of scoring docked ligand conformations using free energy correlations. Eur. J. Med. Chem. 42, 921-933.
47. Spyrakis, F., Cozzini, P., Bertoli, C., Marabotti, A., Kellogg, G. E., and Mozzarelli, A. (2007) Energetics of the protein-DNA-water interaction. BMC Struct. Biol. 7, 4.
48. Spyrakis, F., Fornabaio, M., Cozzini, P., Mozzarelli, A., Abraham, D. J., and Kellogg, G. E. (2004) Computational titration analysis of a multiprotic HIV-1 protease-ligand complex. J. Am. Chem. Soc. 126, 11764-11765.
49. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., and Bourne, P. E. (2000) The Protein Data Bank. Nucleic Acids Res. 28, 235-242.
50. Cheng, Y., and Prusoff, W. (1973) Relationship between the inhibition constant (Kl) and the concentration of inhibitor which causes 50% inhibition (150) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099-3108.
51. Amadasi, A., Cozzini, P., Incerti, M., Duce, E., Fisicaro, E., and Vicini, P. (2007) Molecular modeling of binding between amidi- nobenzisothiazoles, with antidegenerative activity on cartilage, and matrix metalloproteinase-3. Bioorg. Med. Chem. 15, 1420-1429.
52. Porotto, M., Fornabaio, M., Greengard, O., Murrell, M. T., Kellogg, G. E., and Moscona, A. (2006) Paramyxovirus receptor-binding molecules: Engagement of one site on the hemagglutinin-neuraminidase protein modulates activity at the second site. J. Virol. 80, 1204-1213.
53. Hansch, C., and Leo, A. J. (1979) Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley and Sons Inc., New York.
54. Derewenda, Z. S., Lee, L., and Derewenda, U. (1995) The occurrence of C-H-O hydrogen bonds in proteins. J Mol. Biol. 252, 248-262.
55. Vargas, R., Garza, J., Dixon, D. A., and Hay, B. P. (2000) How strong is the C-H-O=C hydrogen bond? J. Am. Chem. Soc. 122, 4750-4755.
56. Perola, E., Walters, W. P., and Charifson, P. S. (2004) A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance. Proteins 56, 235-249.
57. Ciana, P., Di Luccio, G., Belcredito, S., Pollio, G., Vegeto, E., Tatangelo, L., Tiveron, C., and Maggi, A. (2001) Engineering of a mouse for the in vivo profiling of estrogen receptor activity. Mol. Endocrinol. 15, 1104-1113.
58. Capra, V., Veltri, A., Foglia, C., Crimaldi, L., Habib, A., Parenti, M., and Rovati, G. (2004) Mutational analysis of the highly conserved ERY motif of the thromboxane A2 receptor: Alternative role in G protein-coupled receptor signaling. Mol. Pharmacol. 66, 880-889.
59. Stahl, M., and Bohm, H. J. (1998) Development of filter functions for protein-ligand docking. J. Mol. Graphics Modell. 16, 121-132.
60. Nicholls, A., Sharp, K. A., and Honig, B. (1991) Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins 11, 281-296.
61. Gruneberg, S., Stubbs, M. T., and Klebe, G. (2002) Successful virtual screening for novel inhibitors of human carbonic anhydrase: Strategy and experimental confirmation. J. Med. Chem. 45, 3588-3602.
62. Lyne, P. D. (2002) Structure-based virtual screening: an overview. Drug Discovery Today 7, 1047-1055.
63. Burnett, J. C., Botti, P., Abraham, D. J., and Kellogg, G. E. (2001) Computationally accessible method for estimating free energy changes resulting from site-specific mutations of biomolecules: Systematic model building and structural/hydropathic analysis of deoxy and oxy hemoglobins. Proteins 42, 355-377.
64. Cummings, M. D., Des Jarlais, R. L., Gibbs, A. C, Mohan, V., and Jaeger, E. P. (2005) Comparison of automated docking programs as virtual screening tools. J. Med. Chem. 48, 962-976.
65. Graves, A. P., Brenk, R., and Shoichet, B. K. (2005) Decoys for docking. J. Med. Chem. 48, 3714-3728.
66. Stahl, M., and Rarey, M. (2001) Detailed analysis of scoring functions for virtual screening. J. Med. Chem. 44, 1035-1042.
67. Warren, G. L., Andrews, C. W., Capelli, A. M., Clarke, B., LaLonde, J., Lambert, M. H., Lindvall, M., Nevins, N., Semus, S. F., Senger, S., Tedesco, G., Wall, I. D., Woolven, J. M., Peishoff, C. E., and Head, M. S. (2006) A critical assessment of docking programs and scoring functions. J Med. Chem. 49, 5912-5931.
68. Charifson, P. S., Corkery, J. J., Murcko, M. A., and Walters, W. P. (1999) Consensus scoring: A method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins. J. Med. Chem. 42, 5100-5109.
69. Feher, M. (2006) Consensus scoring for protein-ligand interactions. Drug Discovery Today 11, 421-428.
70. Hoffmann, D., Kramer, B., Washio, T., Steinmetzer, T., Rarey, M., and Lengauer, T. (1999) Two-stage method for protein-ligand docking. J. Med. Chem. 42, 4422-4433.
71. Evers, A., and Klebe, G. (2004) Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. J. Med. Chem. 47, 5381-5392.
72. Kellenberger, E., Springael, J. Y., Parmentier, M., Hachet-Haas, M., Galzi, J. L., and Rognan, D. (2007) Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening. J. Med. Chem 50, 1294-1303.
73. Lyne, P. D., Kenny, P. W., Cosgrove, D. A., Deng, C., Zabludoff, S., Wendoloski, J. J., and Ashwell, S. (2004) Identification of compounds with nanomolar binding affinity for checkpoint kinase-1 using knowledge-based virtual screening. J. Med. Chem. 47, 1962-1968.
74. Fujimoto, N., Kohta, R., Kitamura, S., and Honda, H. (2004) Estrogenic activity of an antioxidant, nordihydroguaiaretic acid (NDGA). Life Sci. 74, 1417-1425.
75. Anstead, G. M., Carlson, K. E., and Katzenellenbogen, J. A. (1997) The estradiol pharmacophore: ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids 62, 268-303.
76. Shoichet, B. K. (2004) Virtual screening of chemical libraries. Nature 432, 862-865.
77. Klebe, G. (2006) Virtual ligand screening: strategies, perspectives and limitations. Drug Discovery Today 11, 580-594.
78. ter Veld, M. G., Schouten, B., Louisse, J., van Es, D. S., van der Saag, P. T., Rietjens, I. M., and Murk, A. J. (2006) Estrogenic potency of food-packaging-associated plasticizers and antioxidants as detected in ERa and ERβ reporter gene cell lines. J. Agric. Food Chem. 54, 4407-4416.
79. Manas, E. S., Xu, Z. B., Unwalla, R. J., and Somers, W. S. (2004) Understanding the selectivity of genistein for human estrogen receptor-beta using X-ray crystallography and computational methods. Structure 12, 2197-2207.
80. Kim, S., Wu, J. Y., Birzin, E. T., Frisch, K., Chan, W., Pai, L. Y., Yang, Y. T., Mosley, R. T., Fitzgerald, P. M., Sharma, N., Dahllund, J., Thorsell, A. G., DiNinno, F., Rohrer, S. P., Schaeffer, J. M., and Hammond, M. L. (2004) Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor alpha modulators. J. Med. Chem. 47, 2171-2175.
81. Blizzard, T. A., Dininno, F., Morgan, J. D., 2nd, Chen, H. Y., Wu, J. Y., Kim, S., Chan, W., Birzin, E. T., Yang, Y. T., Pai, L. Y., Fitzgerald, P. M., Sharma, N., Li, Y., Zhang, Z., Hayes, E. C., Dasilva, C. A., Tang, W., Rohrer, S. P., Schaeffer, J. M., and Hammond, M. L. (2005) Estrogen receptor ligands. Part 9: Dihy-drobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers. Bioorg. Med. Chem. Lett. 15, 107-113.
82. Tan, Q., Blizzard, T. A., Morgan, J. D., 2nd, Birzin, E. T., Chan, W., Yang, Y. T., Pai, L. Y., Hayes, E. C, DaSilva, C. A., Warrier, S., Yudkovitz, J., Wilkinson, H. A., Sharma, N., Fitzgerald, P. M., Li, S., Colwell, L., Fisher, J. E., Adamski, S., Reszka, A. A., Kimmel, D., DiNinno, F., Rohrer, S. P., Freedman, L. P., Schaeffer, J. M., and Hammond, M. L. (2005) Estrogen receptor ligands. Part 10: Chromanes: Old scaffolds for new SERAMs. Bioorg. Med. Chem. Lett. 15, 1675-1681.
83. Manas, E. S., Unwalla, R. J., Xu, Z. B., Malamas, M. S., Miller, C. P., Harris, H. A., Hsiao, C., Akopian, T., Hum, W. T., Malakian, K., Wolfrom, S., Bapat, A., Bhat, R. A., Stahl, M. L., Somers, W. S., and Alvarez, J. C. (2004) Structure-based design of estrogen receptor-beta selective ligands. J. Am. Chem. Soc. 126, 15106-15119.
84. Renaud, J., Bischoff, S. F., Buhl, T., Floersheim, P., Fournier, B., Geiser, M., Halleux, C., Kallen, J., Keller, H., and Ramage, P. (2005) Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands. J. Med. Chem. 48, 364-379.
85. Shiau, A. K., Barstad, D., Radek, J. T., Meyers, M. J., Nettles, K. W., Katzenellenbogen, B. S., Katzenellenbogen, J. A., Agard, D. A., and Greene, G. L. (2002) Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat. Struct. Biol. 9, 359-364.
86. Hsieh, R. W., Rajan, S. S., Sharma, S. K., Guo, Y., DeSombre, E. R., Mrksich, M., and Greene, G. L. (2006) Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity. J. Biol. Chem. 281, 17909-17919.
87. Norman, B. H., Dodge, J. A., Richardson, T. I., Borromeo, P. S., Lugar, C. W., Jones, S. A., Chen, K., Wang, Y., Durst, G. L., Barr, R. J., Montrose-Rafizadeh, C, Osborne, H. E., Amos, R. M., Guo, S., Boodhoo, A., and Krishnan, V. (2006) Benzopyrans are selective estrogen receptor beta agonists with novel activity in models of benign prostatic hyperplasia. J. Med. Chem. 49, 6155-6157.
88. Wu, Y. L., Yang, X., Ren, Z., McDonnell, D. P., Norris, J. D., Willson, T. M., and Greene, G. L. (2005) Structural basis for an unexpected mode of SERM-mediated ER antagonism. Mol. Cell 18, 413-424.
89. Richardson, T. I., Dodge, J. A., Durst, G. L., Pfeifer, L. A., Shah, J., Wang, Y., Durbin, J. D., Krishnan, V., and Norman, B. H. (2007) Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 3: Synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification. Bioorg. Med. Chem. Lett. 17, 4824-4828.
90. Norman, B. H., Richardson, T. I., Dodge, J. A., Pfeifer, L. A., Durst, G. L., Wang, Y., Durbin, J. D., Krishnan, V., Dinn, S. R., Liu, S., Reilly, J. E., and Ryter, K. T. (2007) Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 4: Functionalization of the benzopyran A-ring. Bioorg. Med. Chem. Lett. 17, 5082-5085.
91. Nettles, K. W., Bruning, J. B., Gil, G., O'Neill, E. E., Nowak, J., Guo, Y., Kim, Y., DeSombre, E. R., Dilis, R., Hanson, R. N., Joachimiak, A., and Greene, G. L. (2007) Structural plasticity in the oestrogen receptor ligand-binding domain. EMBO Rep. 8, 563-568.
92. Hummel, C. W., Geiser, A. G., Bryant, H. U., Cohen, I. R., Dally, R. D., Fong, K. C., Frank, S. A., Hinklin, R., Jones, S. A., Lewis, G., McCann, D. J., Rudmann, D. G., Shepherd, T. A., Tian, H., Wallace, O. B., Wang, M., Wang, Y., and Dodge, J. A. (2005) A selective estrogen receptor modulator designed for the treatment of uterine leiomyoma with unique tissue specificity for uterus and ovaries in rats. J. Med. Chem. 48, 6772-6775.
93. Dykstra, K. D., Guo, L., Birzin, E. T., Chan, W., Yang, Y. T., Hayes, E. C, DaSilva, C. A., Pai, L. Y., Mosley, R. T., Kraker, B., Fitzgerald, P. M., DiNinno, F., Rohrer, S. P., Schaeffer, J. M., and Hammond, M. L. (2007) Estrogen receptor ligands. Part 16: 2-Aryl indoles as highly subtype selective ligands for ERalpha. Bioorg. Med. Chem. Lett. 17, 2322-2328.
94. Kuiper, G. G., Carlsson, B., Grandien, K., Enmark, E., Haggblad, J., Nilsson, S., and Gustafsson, J. A. (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863-870.
95. Chen, H. Y., Dykstra, K. D., Birzin, E. T., Frisch, K., Chan, W., Yang, Y. T., Mosley, R. T., DiNinno, F., Rohrer, S. P., Schaeffer, J. M., and Hammond, M. L. (2004) Estrogen receptor ligands. Part 1: The discovery of flavanoids with subtype selectivity. Bioorg. Med Chem. Lett. 14, 1417-1421.
96. Amari, G., Armani, E., Ghirardi, S., Delcanale, M., Civelli, M., Caruso, P. L., Galbiati, E., Lipreri, M., Rivara, S., Lodola, A., and Mor, M. (2004) Synthesis, pharmacological evaluation, and structure-activity relationships of benzopyran derivatives with potent SERM activity. Bioorg. Med. Chem. 12, 3763-3782.
97. Gauthier, S., Caron, B., Cloutier, J., Dory, Y. L., Favre, A., Larouche, D., Mailhot, J., Ouellet, C., Schwerdtfeger, A., Leblanc, G., Martel, C., Simard, J., Merand, Y., Belanger, A., Labrie, C., and Labrie, F. (1997)(S)-(+)4-[7-(2,2-Dimethyl-l-oxopropoxy)-4-methyI-2-[4-[2- (1-piperidinyl)- ethoxy]phenyl]-2H-l-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate (EM-800): A highly potent, specific, and orally active nonsteroidal antiestrogen. J. Med. Chem. 40, 2117-2122.
98. Suh, N., Glasebrook, A. L., Palkowitz, A. D., Bryant, H. U., Burris, L. L., Starling, J. J., Pearce, H. L., Williams, C., Peer, C., Wang, Y., and Sporn, M. B. (2001) Arzoxifene, a new selective estrogen receptor modulator for chemoprevention of experimental breast cancer. Cancer Res. 61, 8412-8415.
99. Miller, C. P., Collini, M. D., Tran, B. D., Harris, H. A., Kharode, Y. P., Marzolf, J. T., Moran, R. A., Henderson, R. A., Bender, R. H., Unwalla, R. J., Greenberger, L. M., Yardley, J. P., Abou-Gharbia, M. A., Lyttle, C. R., and Koram, B. S. (2001) Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J. Med. Chem. 44, 1654-1657.
100. Rosati, R. L., Da Silva Jardine, P., Cameron, K. O., Thompson, D. D., Ke, H. Z., Toler, S. M., Brown, T. A., Pan, L. C., Ebbinghaus, C. F., Reinhold, A. R., Elliott, N. C., Newhouse, B. N., Tjoa, C. M., Sweetnam, P. M., Cole, M. J., Arriola, M. W., Gauthier, J. W., Crawford, D. T., Nickerson, D. F., Pirie, C. M., Qi, H., Simmons, H. A., and Tkalcevic, G. T. (1998) Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J. Med. Chem, 41, 2928-2931.
101. Meyers, M. J., Sun, J., Carlson, K. E., Katzenellenbogen, B. S., and Katzenellenbogen, J. A. (1999) Estrogen receptor subtype-selective ligands: asymmetric synthesis and biological evaluation of cis- and trans-5,ll-dialkyl-5,6,l 1,12-tetrahydrochrysenes.J. Med. Chem. 42, 2456-2468.
102. Blizzard, T. A., Morgan, J. D., 2nd, Mosley, R. T., Birzin, E. T., Frisch, K., Rohrer, S. P., and Hammond, M. L. (2003) 2-Phenyl-spiroindenes: A novel class of selective estrogen receptor modulators (SERMs). Bioorg. Med. Chem, Lett. 13, 479-483.
103. Jobling, S., Reynolds, T., White, R., Parker, M. G., and Sumpter, J. P. (1995) A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ. Health Perspect. 103, 582-587.