Conformational studies of novel estrogen receptor ligands by 1D and 2D NMR spectroscopy and computational methods

The solution conformations of the novel estrogen receptor ligands (17alpha,20E)-(p-trifluoromethylphenyl)vinylestradiol (1) and (17a,20E)-(o-trifluoromethylphenyl)vinylestradioI (2) were investigated in 2D and 1D NOESY studies and by comparison of C-13 NMR chemical shifts with theoretical shieldings. The H-1 and C-13 assignments of 1 and 2 were determined by DEPT, COSY and HMQC experiments. The conformations of the 17alpha-phenylvinyl substituents of 1 and 2 are of interest because of their differing receptor binding affinities and effects in in vivo uterotrophic growth assays. A statistical method of evaluating contributing conformers of 1 and 2 from predicted C-13 shifts of possible structures correlated fairly well with conformational conclusions derived from the NOE data. The 17alpha substituents of 1 and 2 apparently exist in similar conformational equilibria, suggesting that while 1 and 2 would occupy a similar receptor volume, interactions with the protein may shift the equilibrium and thereby influence the expression of the ligand. Copyright (C) 2003 John Wiley Sons, Ltd.