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 language | English (US) |
|---|---|
| Pages (from-to) | 6321-6336 |
| Number of pages | 16 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 60 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 27 2017 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells. / 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.
In: Journal of Medicinal Chemistry, Vol. 60, No. 14, 27.07.2017, p. 6321-6336.Research output: Contribution to journal › Article
}
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.
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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UR - http://www.scopus.com/inward/citedby.url?scp=85026362122&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.7b00585
DO - 10.1021/acs.jmedchem.7b00585
M3 - Article
VL - 60
SP - 6321
EP - 6336
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -