Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells

• Published in: Journal of medicinal chemistry 2017-07, Vol.60 (14), p.6321-6336
• Main Authors: Min, Jian, Guillen, Valeria Sanabria, Sharma, Abhishek, Zhao, Yuechao, Ziegler, Yvonne, Gong, Ping, Mayne, Christopher G, Srinivasan, Sathish, Kim, Sung Hoon, Carlson, Kathryn E, Nettles, Kendall W, Katzenellenbogen, Benita S, Katzenellenbogen, John A
• Format: Article
• Language: English
• Subjects: Acrylamides - chemical synthesis; Acrylamides - pharmacology; Adamantane - analogs & derivatives; Adamantane - chemical synthesis; Adamantane - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Breast Neoplasms - drug therapy; Cell Line, Tumor; Cell Proliferation - drug effects; Down-Regulation; Drug Screening Assays, Antitumor; Esters - chemical synthesis; Esters - pharmacology; Estrogen Antagonists - chemical synthesis; Estrogen Antagonists - pharmacology; Estrogen Receptor alpha - metabolism; Female; Humans; Ketones - chemical synthesis; Ketones - pharmacology; Radioligand Assay; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00585

To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and amide analogs. All compounds were high affinity estrogen receptor α (ERα) ligands but displayed a range of efficacies and potencies as antiproliferative and ERα-downregulating agents. There were large differences in activity between compounds having minor structural changes, but antiproliferative and ERα-downregulating efficacies generally paralleled one another. Some compounds with side chain polar groups had particularly high affinities. The secondary carboxamides had the best cellular activities, and the 3-hydroxypropylamide was as efficacious as fulvestrant in suppressing cell proliferation and gene expression. This study has produced structurally novel antiestrogens based on a simple adamantyl core structure with acrylate side chains optimized for cellular antagonist activity.