title: Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors.
abstract: A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.
authors.forename: Jinzhong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: O'Neill
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Ge
authors.initials: G
authors.lastname: Yu
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000096:biosynthesis / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000187:drug effects; D005260:Female; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010636:Phenols; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; D020845:Selective Estrogen Receptor Modulators; D013267:Stilbenes