TY - JOUR
T1 - Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells
AU - Min, Jian
AU - Guillen, Valeria Sanabria
AU - Sharma, Abhishek
AU - Zhao, Yuechao
AU - Ziegler, Yvonne
AU - Gong, Ping
AU - Mayne, Christopher G.
AU - Srinivasan, Sathish
AU - Kim, Sung Hoon
AU - Carlson, Kathryn E.
AU - Nettles, Kendall W.
AU - Katzenellenbogen, Benita S.
AU - Katzenellenbogen, John A.
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/7/27
Y1 - 2017/7/27
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.7b00585
DO - 10.1021/acs.jmedchem.7b00585
M3 - Article
C2 - 28657320
AN - SCOPUS:85026362122
SN - 0022-2623
VL - 60
SP - 6321
EP - 6336
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -