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Biomedicines 2016, 4(3), 15; doi:10.3390/biomedicines4030015

Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

1
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland
2
School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Dublin 2, Ireland
3
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Dublin 2, Ireland
4
Division of Health Sciences, University of South Australia, Adelaide SA 5000, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Michael A. Firer
Received: 1 May 2016 / Revised: 21 June 2016 / Accepted: 7 July 2016 / Published: 20 July 2016
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Abstract

Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. A series of ER ligand conjugates were synthesised incorporating an antagonistic ER ligand scaffold based on endoxifen, covalently-bound via an amide linkage to a variety of combretastatin-based analogues, which may act as antimitotic agents. These novel endoxifen-combretastatin hybrid scaffold analogues were biochemically evaluated in order to determine their antiproliferative and cytotoxicity effects in both the ER-positive MCF-7 and the ER-negative MDA-MB-231 human breast cancer cell lines. ER competitive binding assays were carried out to assess the binding affinity of the lead conjugate 28 towards both the ERα and ERβ isoforms. In results from the NCI 60-cell line screen, the lead conjugate 28 displayed potent and highly selective antiproliferative activity towards the MCF-7 human cancer cell line (IC50 = 5 nM). In the ER-binding assays, the lead conjugate 28 demonstrated potent ER competitive binding in ERα (IC50 value: 0.9 nM) and ERβ (IC50 value: 4.7 nM). Preliminary biochemical results also demonstrate that the lead conjugate 28 may exhibit pure antagonism. This series makes an important addition to the class of ER antagonists and may have potential applications in anticancer therapy. View Full-Text
Keywords: estrogen receptor ligands; selective estrogen receptor modulators; tumour targeting; conjugates; tamoxifen; endoxifen; hormone-dependent breast cancer estrogen receptor ligands; selective estrogen receptor modulators; tumour targeting; conjugates; tamoxifen; endoxifen; hormone-dependent breast cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Keely, N.O.; Carr, M.; Yassin, B.; Ana, G.; Lloyd, D.G.; Zisterer, D.; Meegan, M.J. Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold. Biomedicines 2016, 4, 15.

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