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 (17α,20 E )‐( p ‐trifluoromethylphenyl)vinylestradiol ( 1 ) and (17α,20 E )‐( o ‐trifluoromethylphenyl)vinylestradiol ( 2 ) were investigated in 2D and 1D NOESY studies and by comparison of 13 C NMR chemical shifts with theoretical shieldings. The 1 H and 13 C assignments of 1 and 2 were determined by DEPT, COSY and HMQC experiments. The conformations of the 17α‐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 13 C shifts of possible structures correlated fairly well with conformational conclusions derived from the NOE data. The 17α 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 © 2003 John Wiley & Sons, Ltd.