title: A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β.
abstract: The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had good aromatase inhibitory activity (IC50=62.2nM) while also exhibiting good binding activity to both ER-α (EC50=72.1nM) and ER-β (EC50=70.8nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States; School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States; School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China.
authors.forename: Hai-Shan
authors.initials: HS
authors.lastname: Jin
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, IN 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, Indiana Institute for Personalized Medicine, Indianapolis, IN 46202, United States.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, IN 46202, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ipe
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 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, Indiana Institute for Personalized Medicine, Indianapolis, IN 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, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States. Electronic address: cushman@purdue.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D011485:Protein Binding; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D013267:Stilbenes; D001141:Aromatase; C037749:triphenylethylene
keywords: (E,Z)-Norendoxifen synthesis; Antiestrogenic activity; Aromatase inhibitor; Breast cancer; Estrogen receptor