Abstract |
An iron-based cross-dehydrogenative coupling (CDC) approach was applied for the diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators ( SERMs), representing the first application of CDC chemistry in natural product synthesis. The first stage of the two-step synthesis of coumestrol involved a modified aerobic oxidative cross-coupling between ethyl 2-(2,4-dimethoxybenzoyl)acetate and 3-methoxyphenol, with FeCl3 (10 mol%) as the catalyst. The benzofuran coupling product was then subjected to sequential deprotection and lactonization steps, affording the natural product in 59% overall yield. Based on this new methodology other coumestrol analogues were prepared, and their effects on the proliferation of the estrogen receptor (ER)-dependent MCF-7 and of the ER-independent MDA-MB-231 breast cancer cells were tested. As a result, new types of estrogen receptor ligands having an acetamide group instead of the 9-hydroxyl group of coumestrol were discovered. Both 9-acetamido-coumestrol and 8-acetamidocoumestrol were found more active than the natural product against estrogen-dependent MCF-7 breast cancer cells, with IC50 values of 30 and 9 nM, respectively.
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Authors | Umesh A Kshirsagar, Regev Parnes, Hagit Goldshtein, Rivka Ofir, Raz Zarivach, Doron Pappo |
Journal | Chemistry (Weinheim an der Bergstrasse, Germany)
(Chemistry)
Vol. 19
Issue 40
Pg. 13575-83
(Sep 27 2013)
ISSN: 1521-3765 [Electronic] Germany |
PMID | 23946113
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Chemical References |
- 8-acetamido-coumestrol
- 9-acetamido-coumestrol
- Antineoplastic Agents
- ESR1 protein, human
- Estrogen Receptor Modulators
- Estrogen Receptor alpha
- Receptors, Estrogen
- Selective Estrogen Receptor Modulators
- Iron
- Coumestrol
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Topics |
- Antineoplastic Agents
(chemistry, pharmacology)
- Breast Neoplasms
(drug therapy)
- Cell Line, Tumor
- Coumestrol
(analogs & derivatives, chemistry, pharmacology)
- Estrogen Receptor Modulators
(chemistry, pharmacology)
- Estrogen Receptor alpha
(chemistry)
- Female
- Humans
- Inhibitory Concentration 50
- Iron
(chemistry)
- Molecular Structure
- Receptors, Estrogen
(chemistry)
- Selective Estrogen Receptor Modulators
(chemistry, pharmacology)
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