Potential steroidal antiestrogens.
A series of analogues of 17beta-estradiol has been synthesized and the compounds have been tested, using sucrose density gradient analysis, for their ability to compete with [6,7-3H]-17beta-estradiol for the estrogen-receptor protein from mouse uterine homogenates. Active compounds were also tested for antiuterotrophic activity in immature rats and/or mice. 3,17beta-Dihydroxy-6-phenylestra-1,3,5(10),6-tetraene (14) was the most active new compound in the in vitro test suppressing the binding of 17beta-estradiol by 34 and 87%, respectively, at molar ratios of 1 and 3.16. It was significantly more potent than the intermediate 6-oxoestradiol (4) which produced a 52% inhibition of binding at a molar ratio of 3.16. The thiosemicarbazone of 6-oxoestradiol (17) and the derived 3,17beta-dihydroxy-6-(2-imino-4-oxothiazolidinyl-1-imino)estra-1,3,5(10)-triene (19) produced, respectively, only 46 and 16% inhibition of binding at a molar ratio of 10. Introduction of a 1-methyl substituent into either 6-oxo or 6-phenyl compounds reduced affinity for the receptor significantly (compounds 5 and 15) and conversion of the 3-OH into a beta-dialkylaminoethoxy group virtually destroyed all binding activity (compounds 2, 6, 10, and 11). At a molar ratio of 10 compound 14 failed to suppress the uterine weight response of immature rats to 17beta-estradiol, whereas compound 15, at a molar ratio of 200, produced a significant increase in the uterine weight of immature rats but not of immature mice even at a molar ratio of 1000.
D000818:Animals; D001667:Binding, Competitive; D003600:Cytosol / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D004958:Estradiol