Aerobic iron-based cross-dehydrogenative coupling enables efficient diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators.
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.
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105 (Israel), Fax: (+972) 8-6428693.
Umesh A
UA
Kshirsagar
Regev
R
Parnes
Hagit
H
Goldshtein
Rivka
R
Ofir
Raz
R
Zarivach
Doron
D
Pappo
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003375:Coumestrol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007501:Iron / Q000737:chemistry*; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000737:chemistry*; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology*
C000588714:8-acetamido-coumestrol; C000588713:9-acetamido-coumestrol; D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D007501:Iron; D003375:Coumestrol
cross-coupling; iron; natural products; structure-activity relationships; total synthesis