Abstract
The estrogen receptors (ERα and ERβ ), are ligand inducible nuclear receptors which play a key role in many cellular functions through specific gene expression regulation. The estrogen receptor is regarded as an attractive therapeutic target for hormone-dependent breast cancers. The antiestrogen drug tamoxifen is useful in the treatment of breast cancer. To develop new ER targeting agents as probes of estrogen receptor action, the synthesis and preliminary biochemical evaluation of five structurally varied estrogen receptor ligand conjugates containing the tamoxifen metabolite endoxifen are now reported. These structurally varied conjugates bind to the estrogen receptor (commonly overexpressed in breast cancer cells) and contain DNA alkylating, aromatase inhibitor and COX2 inhibitor moieties. The ER targeting group endoxifen (E/Z 4-hydroxy-N-desmethyltamoxifen) was selected for its ability to bind to the estrogen receptor. Compound 11 exhibited moderate antiproliferative activity IC50 = 1.64 μM in MCF-7 breast cancer cells, while compound 9b demonstrated the most potent ER binding effects with IC50 values of 35.6 nM(ERα), 19.5 nM(ERβ ).
Keywords: Estrogen receptor, Conjugates, Tamoxifen, Tumour targeting, Antiproliferative activity, Breast cancer, Nuclear receptors, Tumour Targeting Agents, ER, Chlorambucil, antiproliferative enhanced activity, Alkylating agents, alkaloid ellipticine, acrylonitrile combretastatin analogue 5, AEBS, endoxifen conjugates
Letters in Drug Design & Discovery
Title: Design, Synthesis and Biochemical Evaluation of Estrogen Receptor Ligand Conjugates as Tumour Targeting Agents
Volume: 9 Issue: 3
Author(s): Niall O. Keely, Daniela M. Zisterer and Mary J. Meegan
Affiliation:
Keywords: Estrogen receptor, Conjugates, Tamoxifen, Tumour targeting, Antiproliferative activity, Breast cancer, Nuclear receptors, Tumour Targeting Agents, ER, Chlorambucil, antiproliferative enhanced activity, Alkylating agents, alkaloid ellipticine, acrylonitrile combretastatin analogue 5, AEBS, endoxifen conjugates
Abstract: The estrogen receptors (ERα and ERβ ), are ligand inducible nuclear receptors which play a key role in many cellular functions through specific gene expression regulation. The estrogen receptor is regarded as an attractive therapeutic target for hormone-dependent breast cancers. The antiestrogen drug tamoxifen is useful in the treatment of breast cancer. To develop new ER targeting agents as probes of estrogen receptor action, the synthesis and preliminary biochemical evaluation of five structurally varied estrogen receptor ligand conjugates containing the tamoxifen metabolite endoxifen are now reported. These structurally varied conjugates bind to the estrogen receptor (commonly overexpressed in breast cancer cells) and contain DNA alkylating, aromatase inhibitor and COX2 inhibitor moieties. The ER targeting group endoxifen (E/Z 4-hydroxy-N-desmethyltamoxifen) was selected for its ability to bind to the estrogen receptor. Compound 11 exhibited moderate antiproliferative activity IC50 = 1.64 μM in MCF-7 breast cancer cells, while compound 9b demonstrated the most potent ER binding effects with IC50 values of 35.6 nM(ERα), 19.5 nM(ERβ ).
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Cite this article as:
O. Keely Niall, M. Zisterer Daniela and J. Meegan Mary, Design, Synthesis and Biochemical Evaluation of Estrogen Receptor Ligand Conjugates as Tumour Targeting Agents, Letters in Drug Design & Discovery 2012; 9 (3) . https://dx.doi.org/10.2174/157018012799129864
DOI https://dx.doi.org/10.2174/157018012799129864 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
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