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

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.