Novel high-affinity steroidal estrogenic ligands:: Synthesis and receptor binding of 11β-vinyl-17α-E/Z-phenylselenovinyl estradiols

previous studies from our laboratory demonstrated separately the tolerance of the estrogen receptor for the 17 alpha-phenylselenovinyl substituent and the enhancement of affinity imparted by the 11 beta-vinyl moiety. Our recent publication suggested that the two groups could be combined within a single structure and retain high affinity for the estrogen receptor. As a result we have prepared in good overall yields the E- and Z-isomers of 11 beta-vinyl-17 alpha-phenylselenovinyl estradiol. Evaluation of the new steroids with receptor isolated from lamb cytosol indicated that both isomers are poorer ligands than estradiol at 4 degrees C, but both are better than estradiol at 25 degrees C. This behavior had not been observed for the 11 beta-unsubstituted 17 alpha-E/Z phenylselenovinyl estradiols. Of particular interest was the observation that unlike previous isomer pairs, the E-isomer possessed a greater affinity than the Z-isomer. The results suggest that relatively small changes iii structure may impart significant differences in the interactions with the receptor and provide the basis for further ligand design. (C) 1998 by Elsevier Science Inc.