title: Estrogen to antiestrogen with a single methylene group resulting in an unusual steroidal selective estrogen receptor modulator.
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 this critical structure, presenting the possibility that it might act through a unique mechanism.
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jing-Xin
authors.initials: JX
authors.lastname: Zhang
authors.forename: David C
authors.initials: DC
authors.lastname: Labaree
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hochberg
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000819:agonists; D005260:Female; D006801:Humans; D006838:Hydrocarbons; D008697:Methane / Q000031:analogs & derivatives*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology*; D014162:Transfection; D014599:Uterus / Q000187:drug effects / Q000473:pathology
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D006838:Hydrocarbons; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C488278:ethyl (3,17-dihydroxyestra-1,3,5(10)-triene-11-yl)acetate; C488305:methyl (3,17-dihydroxyestra-1,3,5(10)-triene-11-yl)acetate; C030011:carbene; D004958:Estradiol; D002784:Cholesterol; D008697:Methane