Synthesis and evaluation of (17alpha,20Z)-21-(4-substituted-phenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17beta-diols as ligands for the estrogen receptor-alpha hormone binding domain: comparison with 20E-isomers.
As part of our ongoing program to develop probes for the hormone binding domain of the estrogen receptor-alpha (ERalpha), we prepared and evaluated a series of 17alpha,Z-(4-substituted-phenyl)vinyl estradiol derivatives. The results indicated that the relative binding affinities (RBAs) at 25 degrees C for the new compounds were significant (RBA = 9-57) although less than that of estradiol (RBA = 100) or of the parent unsubstituted phenylvinyl estradiol (RBA = 66). All of the Z-compounds were full agonists in the uterotrophic assay, indicating that the ligands formed estrogen-like complexes with the estrogen receptor-alpha hormone binding domain (ERalpha-HBD). Comparison of corresponding Z- and E-4-substituted phenylvinyl ligands complexed with the ERalpha-HBD indicated small but significant differences in binding modes that may account for the differing trends seen in the structure-activity relationships for the two series.
Department of Chemistry, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115-5000, USA. r.hanson@neu.edu
Robert N
RN
Hanson
Carolyn J
CJ
Friel
Robert
R
Dilis
Alun
A
Hughes
Eugene R
ER
DeSombre
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D007202:Indicators and Reagents; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009651:Norpregnatrienes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding
D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D007202:Indicators and Reagents; D008024:Ligands; D009651:Norpregnatrienes