Synthesis and estrogen receptor binding of (17 alpha, 20E)- and (17 alpha, 20Z)-21-phenylthio- and 21-phenylseleno-19-norpregna-1,3,5(10),20-tetraene-3,17 beta-diols.
Previous studies from our laboratory using 17 alpha-E- and 17 alpha-Z-halovinyl estradiols demonstrated a marked enhancement of receptor binding by the Z-isomers. This suggested tolerance at the 17 alpha-position was not previously observed by investigations using 16 alpha and 17 alpha-substituted estradiols. Because of the synthetic access provided by vinyl tin chemistry, we prepared the 17 alpha-E and Z-phenylthiovinyl and phenylselenovinyl estradiols and compared their binding characteristics to those of the previously reported 16 alpha/17 alpha-phenylseleno and methylseleno estradiols. The results, in addition to demonstrating a facile preparation of the target compounds, indicated that significant receptor affinity was retained by these compounds (relative binding affinity = 24.5-117). The highest affinity was demonstrated by the 17 alpha-Z-phenylthiovinyl estradiol 5a, which, by molecular modeling, exhibited a significantly different molecular conformation from the corresponding 17 alpha-E-phenylthiovinyl isomer or the 17 alpha-phenyl-thioethynyl analog. The current series possessed better binding characteristics than the phenylseleno and methylseleno estradiols but somewhat poorer binding than the 17 alpha-E/Z-halovinyl series. The observations suggest that some steric limitations exist in a portion of the 17 alpha-region, and that the region is better accessed by compounds possessing Z-vinyl stereochemistry.
Napolitano
E
E
Department of Pharmaceutical Sciences, Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston, Massachusetts 02115, USA.
Fiaschi
R
R
Herman
L W
LW
Hanson
R N
RN
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D008958:Models, Molecular; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014599:Uterus / Q000737:chemistry
D011960:Receptors, Estrogen; D004958:Estradiol