A, Lee WH, Montes MO, Villoutreix BO. J Med Chem. 2005; 48:6012. [PubMed: 16162004] 32. Norman BH, Richardson TI, Dodge JA, Pfeifer LA, Durst GL, Wang Y, Durbin JD, Krishnan V, Dinn SR, Liu S, Reilly JE, Ryter KT. Bioorg Med Chem Lett. 2007; 17:5082. [PubMed: 17662603] 33. Shiau AK, Barstad D, Radek JT, Meyers MJ, Nettles KW, Katzenellenbogen BS, Katzellenbogen JA, Agard DA, Greene GL. Nat Struct Biol. 2002; 9:359. [PubMed: 11953755] 34. Tuccinardi T, Bertini S, Martinelli A, Minutolo F, Ortore G, Placanica G, Prota G, Rapposelli S, Carleson KE, Katzenellenbogen JA, Macchia M. J Med Chem. 2006; 49:5001. [PubMed: 16884312] 35. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. J Comput Chem. 2009; 30:2785. [PubMed: 19399780] 36. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ.661487-17-8 Data Sheet J Comput Chem. 1998; 19:1639. 37. Goodsell DS, Morris GM, Olson AJ. J Mol Recognit. 1996; 9:1. [PubMed: 8723313] 38. Huey R, Morris BM, Olson AJ, Goodsell DS. J Comput Chem. 2007; 28:1145. [PubMed: 17274016] 39. Li Z, Zhang H, Gibson M, Li J. Toxicol In Vitro. 2012; 26:769. [PubMed: 22692143]NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptBioorg Med Chem. Author manuscript; out there in PMC 2015 January 01.McCullough et al.PageNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptFigure 1.Structures of 17-estradiol and raloxifene.Bioorg Med Chem. Author manuscript; accessible in PMC 2015 January 01.McCullough et al.PageNIH-PA Author ManuscriptFigure two.NIH-PA Author Manuscript NIH-PA Author ManuscriptLowest energy docking poses from clusters where ligands had been predicted to bind in two modes (A ).Bromocyclobutane Chemscene The human ER estrogen receptor that was used was within the agonist conformation (PDB code 1ere; chain A). Panel C shows the predicted binding orientation for 18 in ER, agonist conformation (PDB code 2jj3; chain A). Panel D shows the predicted binding orientation for 18 in ER, antagonist conformation (PDB code 1l2j; chain A).Bioorg Med Chem. Author manuscript; accessible in PMC 2015 January 01.McCullough et al.PageNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptBioorg Med Chem. Author manuscript; offered in PMC 2015 January 01.PMID:33577449 Scheme 1.Preparation of tetra- and pentacyclic ER analogs (ADD = 1,1-(azodicarbonyl)dipiperidine).McCullough et al.PageNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptBioorg Med Chem. Author manuscript; accessible in PMC 2015 January 01.Scheme 2.Preparation pf p-substituted phenols. Reagents and conditions: (a) 21,Grubbs 1st generation catalyst; (b) H2O2/NaOH; (c) LiAIH4, then 160 ; (d) H2, 20 Pd/C, MeOH; (e) LiAIH4, Et2 O. (See above-mentioned reference for further details.)McCullough et al.PageTableDissociation constants (Kd) in the fluorescence polarization displacement assay and IC50 data from cellbased ER and ER agonist assays and ER antagonist assaysCompound E2 11 4 7 13 two 18 ER Kd (nM) 315 320 ?40 320 ?40 160 ?ten 160 ?ten 32 ?5 1 M ER agonist IC50 (nM) 1.327 NA 92 ?1 NA 484 ?1 145 ?1 NA ER agonist IC50 (nM) 46 pM27 108 ?67 9.8 ?two 88 ?9 111 ?26 six.eight ?0.2 5.4 ?0.3 ER antagonist IC50 (nM) NA 275 ?40 NA 70 ?15 NA NA 137 ?NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptER antagonist behavior was not observed. NA indicates information was not of enough high-quality to measure activity. Assay data for E2 binding to ER,15 and ER agonist and ER agonist and antagonist activity in cellular a.