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: Wei Lv, Jinzhong Liu, Todd C Skaar, Elizaveta O'Neill, Ge Yu, David A Flockhart, Mark Cushman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 59 Issue 1 Pg. 157-70 (Jan 14 2016) ISSN: 1520-4804 [Electronic] United States
• PMID: 26704594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Aromatase Inhibitors
• DNA, Complementary
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Phenols
• RNA, Neoplasm
• Recombinant Proteins
• Selective Estrogen Receptor Modulators
• Stilbenes

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Aromatase Inhibitors (chemical synthesis, pharmacology)
• Catalytic Domain (drug effects)
• Cell Line, Tumor
• DNA, Complementary (biosynthesis, drug effects)
• Estrogen Receptor alpha (drug effects)
• Estrogen Receptor beta (drug effects)
• Female
• Humans
• Microsomes (drug effects, enzymology)
• Models, Molecular
• Molecular Docking Simulation
• Phenols (chemical synthesis, pharmacology)
• RNA, Neoplasm (biosynthesis, drug effects)
• Recombinant Proteins (chemical synthesis, pharmacology)
• Selective Estrogen Receptor Modulators (chemical synthesis, pharmacology)
• Stereoisomerism
• Stilbenes (chemical synthesis, pharmacology)