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

Jian Min, Valeria Sanabria Guillen, Abhishek Sharma, Yuechao Zhao, Yvonne Ziegler, Ping Gong, Christopher G. Mayne, Sathish Srinivasan, Sung Hoon Kim, Kathryn E. Carlson, Kendall W. Nettles, Benita S. Katzenellenbogen, John A. Katzenellenbogen

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6321-6336
Number of pages16
JournalJournal of Medicinal Chemistry
Volume60
Issue number14
DOIs
StatePublished - Jul 27 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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