Nonpolar and short side chain groups at C-11beta of estradiol result in antiestrogens.
We have previously found that esters of 11beta-estradiol carboxylates are transformed from an estrogen into an antiestrogen when the 11beta-side chain is increased in length from four to five non-hydrogen atoms (n > or = 5). To understand the structural requirements for this transformation and obtain metabolically stable analogues that are not susceptible to esterase cleavage, we have synthesized other compounds having an 11beta-side chain composed of other functional groups: ketones, amides, ethers, and thiono esters. With the exception of amides, which bind poorly to the estrogen receptor (ER), all of these compounds exhibit antiestrogenic action when the side chain length is n > or = 5. Ethers (n > or = 5), studied in more detail, inhibit the action of estradiol with either ERalpha or ERbeta. In rat uteri they are estrogen antagonists/weak agonists and decrease the concentration of cholesterol in blood (an hepatic estrogenic action). Thus, these short chain and nonpolar 11beta-analogues of estradiol have tissue specific antiestrogenic/estrogenic actions, characteristics of selective estrogen receptor modulators.
Zhang
Jing-Xin
JX
Department of Obstetrics/Gynecology and Reproductive Sciences, and the Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Labaree
David C
DC
Hochberg
Richard B
RB
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis / Q000494:pharmacology; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
D000577:Amides; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004987:Ethers; D007659:Ketones; D013871:Thiones; D004958:Estradiol; D002784:Cholesterol