Estrogen to antiestrogen with a single methylene group resulting in an unusual steroidal selective estrogen receptor modulator

The Journal of Clinical Endocrinology and Metabolism
Jing-Xin ZhangRichard B Hochberg

Abstract

Selective estrogen receptor (ER) modulators (SERMs) are important therapeutic agents for breast cancer prevention and treatment. We have synthesized two analogs, E11-2,1 [methyl-(3,17beta-dihydroxyestra-1,3,5(10)-triene-11beta-yl)acetate] and E11-2,2 [ethyl-(3,17beta-dihydroxyestra-1,3,5(10)-triene-11beta-yl)acetate], the methyl and ethyl esters of an estradiol analog, substituted in the B ring at C-11beta with a carboxymethyl group. The shorter methyl ester, E11-2,1, has high ER affinity and high estrogenic potency in the Ishikawa estrogen cell bioassay, whereas the longer ethyl ester, E11-2,2, has even higher ER affinity, but little or no estrogenic activity. We found that this minor change of one methylene group transforms a potent estrogenic agonist into an antagonist in vitro with either ER alpha or beta. In the rat, E11-2,2 acts as a SERM in the uterus, where it inhibits estradiol-induced proliferation, and as an estrogen agonist in the liver and skeleton, where it decreases plasma cholesterol and increases bone growth. The characteristic feature of antiestrogens, including SERMs, is a long and polar side-chain that prevents agonist-induced conformation of helix 12 of ER. E11-2,2 with its short, nonpolar side-chain, lacks...Continue Reading

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Citations

Sep 13, 2005·Breast Cancer Research and Treatment·Chun-Xia WangMichael P Digiovanna
Jun 4, 2013·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Jorge Marrero-AlonsoMario Díaz
Feb 10, 2019·Steroids·Nisal Gajadeera, Robert N Hanson

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