Synthesis and evaluation of 11beta-substituted 21-chloro/iodo-(17alpha,20E/Z)-19-norpregna-1,3,5(10),20-te traene-3, 17beta-diols: high-affinity ligands for the estrogen receptor.
We have synthesized six new estrogens substituted at the 11beta-position with a methoxy or vinyl group and at the 17alpha-position with an (E)- or (Z)-chloro/iodovinyl moiety. The products were obtained in good overall yields from the corresponding tri-n-butylstannylvinyl intermediates using the electrophilic halodestannylation methodology. The six new ligands were compared to the 11beta-unsubstituted chloro/iodovinyl derivatives and the 11beta-methoxy (E)- and (Z)-iodovinyl estrogens to evaluate the effects of 11beta-substitution and 20E/Z-stereochemistry. While all the compounds exhibited high affinity for the estrogen receptor, the 20Z-isomers demonstrated higher affinity than the corresponding 20E-isomers. In addition, the presence of the lipophilic 11beta-substituent was favored over either no substituent or a polar (methoxy) group. Within each isomeric series, the presence of the 21-halo substituent had different effects. For the 20E-series, the 21-chloro products had a higher affinity than the 21-iodo analogue, whereas for the 20Z-series the effect was reversed. These results provide additional insights into the interaction of substituted estradiols with the hormone binding domain of the estrogen receptor.
Hanson
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Department of Pharmaceutical Sciences, Bouve College of Pharmacy and Health Sciences, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA.
Napolitano
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Fiaschi
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D000818:Animals; D001665:Binding Sites; D003600:Cytosol / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005260:Female; D008024:Ligands; D011960:Receptors, Estrogen / Q000378:metabolism*; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000378:metabolism / Q000648:ultrastructure
D008024:Ligands; D011960:Receptors, Estrogen; D004958:Estradiol