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Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator

Department of Obstetrics and Gynecology, and Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Dr. Richard B. Hochberg, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520. E-mail: richard.hochberg{at}yale.edu.

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-(3,17ß-dihydroxyestra-1,3,5(10)-triene-11ß-yl)acetate] and E11–2,2 [ethyl-(3,17ß-dihydroxyestra-1,3,5(10)-triene-11ß-yl)acetate], the methyl and ethyl esters of an estradiol analog, substituted in the B ring at C-11ß 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 or ß. 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 this critical structure, presenting the possibility that it might act through a unique mechanism.

This work was supported in part by National Institutes of Health Grants CA-37799 and HL-61432 (to R.B.H.) and CA-92435 (to G.M.) and by the Physiology Core of the Yale Core Center for Musculoskeletal Disorders (P30 Core Center Award AR46032).

Abbreviations: AlkP, Alkaline phosphatase; E₁, estrone; E11–2,1, methyl-(3,17ß-dihydroxyestra-1,3,5(10)-triene-11ß-yl)acetate; E11–2,2, ethyl-(3,17ß-dihydroxyestra-1,3,5(10)-triene-11ß-yl)acetate; E₂, estradiol; ER, estrogen receptor; ERE, ER element; LBD, ligand binding domain; MMA, methymethacrylate; SERM, selective ER modulator; THC, tetrahydrochrysene.