Development of bivalent triarylalkene- and cyclofenil-derived dual estrogen receptor antagonists and downregulators.

Abstract

Up to 80% of mammary carcinoma initially exhibit estrogen-dependent growth, which can be treated by aromatase inhibitors or SERMs/SERDs. To increase the options after failure of the hormonal therapy with these drugs, the search for alternatives with a different mode of action to prevent estrogen action is of high relevance. Therefore, this study focused on the inhibition of coactivator recruitment at the estrogen receptor (ER) by targeted attachment of bivalent compounds at the coactivator binding site besides the primary binding at the ligand binding domain. Eight homodimeric 4-[1-(4-hydroxyphenyl)-2-phenyl-1-butenyl]cinnamic acid (GW7604)- or cyclofenilacrylic acid-based ER ligands with diaminoalkane linkers (C2-C5) were synthesized and their effects on the ER subtypes were assessed in vitro. All compounds possessed full antagonistic potency at ERα/β as determined in a transactivation assay. Furthermore, they exerted medium downregulatory effects dependent on the spacer length and did not stimulate the ER expression as observed for 4-hydroxytamoxifen. The cyclofenil-derived dimer with C4 spacer (15b) showed the highest binding affinity to ERα (RBA = 79.2%) and downregulated the ER content in MCF-7 cells with an efficiency of 38% at 1 μM.

• Authors: Alexandra Knox, Christina Kalchschmid, Daniela Schuster, Francesca Gaggia, Claudia Manzl, Daniel Baecker, Ronald Gust
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 192 Pg. 112191 (Apr 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32169784 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Alkenes
• Estrogen Receptor Antagonists
• Receptors, Estrogen
• Cyclofenil

Topics

• Alkenes (chemical synthesis, chemistry, pharmacology)
• Animals
• COS Cells
• Cell Line, Tumor
• Chlorocebus aethiops
• Cyclofenil (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Development
• Estrogen Receptor Antagonists (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Structure
• Receptors, Estrogen (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship