Aerobic iron-based cross-dehydrogenative coupling enables efficient diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators.

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.

• 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)
• 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

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)