Flexible Estrogen Receptor Modulators:  Design, Synthesis, and Antagonistic Effects in Human MCF-7 Breast Cancer Cells

• Published in: Journal of medicinal chemistry 2001-03, Vol.44 (7), p.1072-1084
• Main Authors: Meegan, Mary J, Hughes, Rosario B, Lloyd, David G, Williams, D. Clive, Zisterer, Daniela M
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Breast Neoplasms; Cell Division - drug effects; Drug Design; Estrogen Antagonists - chemical synthesis; Estrogen Antagonists - chemistry; Estrogen Antagonists - pharmacology; Female; General aspects; Humans; In Vitro Techniques; Ligands; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Estrogen - antagonists & inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured; Uterus - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm001119l

Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds' potential interactions with specific residues within the human estrogen receptor α ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.