A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β

Li-Ming Zhao; Hai-Shan Jin; Jinzhong Liu; Todd C Skaar; Joseph Ipe; Wei Lv; David A Flockhart; Mark Cushman

doi:10.1016/j.bmc.2016.08.064

A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β

Bioorg Med Chem. 2016 Nov 1;24(21):5400-5409. doi: 10.1016/j.bmc.2016.08.064. Epub 2016 Aug 31.

Authors

Li-Ming Zhao¹, Hai-Shan Jin¹, Jinzhong Liu², Todd C Skaar², Joseph Ipe², Wei Lv³, David A Flockhart², Mark Cushman⁴

Affiliations

¹ 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.
² Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, IN 46202, United States.
³ 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.
⁴ 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.

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.

Keywords: (E,Z)-Norendoxifen synthesis; Antiestrogenic activity; Aromatase inhibitor; Breast cancer; Estrogen receptor.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aromatase / metabolism*
Aromatase Inhibitors / chemical synthesis*
Aromatase Inhibitors / chemistry
Aromatase Inhibitors / pharmacology*
Binding Sites / drug effects
Dose-Response Relationship, Drug
Estrogen Receptor alpha / metabolism*
Estrogen Receptor beta / metabolism*
Humans
MCF-7 Cells
Molecular Structure
Protein Binding
Stilbenes / chemical synthesis*
Stilbenes / chemistry
Stilbenes / pharmacology*
Structure-Activity Relationship

Substances

Aromatase Inhibitors
Estrogen Receptor alpha
Estrogen Receptor beta
Stilbenes
Aromatase
triphenylethylene

Grants and funding

P30 CA023168/CA/NCI NIH HHS/United States