Doisynolic-type acids--uterotropically potent estrogens which compete poorly with estradiol for cytosolic estradiol receptors.
Doisynolic acids, a class of seco-steroid acids some of which exhibit greater uterotropic estrogenicity than estradiol-17 beta, are D-ring cleavage products of steroidal estrogens formed by fusion with KOH above 200 degrees C. We have found that electron-transfer reactions between estrone or estradiol and CCl4 or CBrCl3 in KOH-t-BuOH at 25 degrees C rapidly provide 16,16-dichloro- or -dibromodoisynolic acid, respectively, the former approaching estradiol in uterotropic potency. Simple esters from these highly hindered tertiary carboxylic acids, easily prepared via phase-transfer-catalyzed alkylations, also rival estradiol in uterotropic activity. Unlike natural steroidal estrogens or their commonly used artificial equivalents (DES, hexoestrol, ethynylestradiol, etc.) whose uterotropic activity is accompanied by substantial binding affinity for cytosolic estradiol receptors, these highly uterotropic doisynolic-type acids and esters exhibit binding affinities for this receptor of only about 1% that of estradiol-17 beta as determined by the usual competitive binding-inhibition studies with [3H]estradiol. Other highly uterotropic carboxylic acids may exhibit similar characteristics. These unusual results leave open the possibilities that uterotropic seco-steroid and related carboxylic acids undergo some unknown metabolic activation, are exceptionally persistent estrogens, bind to a cytosolic receptor site other than the conventional (type I) estradiol site, or bind directly to type I or type II nuclear receptor sites. At dosages of 1000 times those required for a uterotropic effect, the doisynolic-type acids (24 doses over an 8-week period) were neither toxic nor carcinogenic.
Meyers
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CY
Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale 62901.
Kolb
V M
VM
Gass
G H
GH
Rao
B R
BR
Roos
C F
CF
Dandliker
W B
WB
D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D004963:Estrenes / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011959:Receptors, Estradiol / Q000378:metabolism*; D012632:Secosteroids / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000033:anatomy & histology*; D014621:Vagina / Q000187:drug effects
D004963:Estrenes; D011959:Receptors, Estradiol; D012632:Secosteroids; D004958:Estradiol; C003595:doisynolic acid