Shielding effects at 17α-substituted estrogens. A tentative explanation for the low biological activity of 17α-ethyl-estradiol based on I.R. and NMR spectroscopic studies

Kaspar, Peter; Witzel, Herbert

doi:10.1016/0022-4731(85)90012-3

Cited by 7 publications

(2 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The markedly reduced binding affinity of E 1 for ERs has been suggested previously to reflect the unique importance of the C-17␤ hydroxyl in enhancing its interactions with the ER molecules. This suggestion was also supported by other studies showing that when the C-17␤ hydroxyl of E 2 was converted to a methyl ether or an acetate, their ER binding affinities were greatly diminished (48,49). However, our data also showed that when the entire C-17␤ hydroxyl group was absent, the derivatives [i.e.…”

Section: D-ring Derivativessupporting

confidence: 86%

Quantitative Structure-Activity Relationship of Various Endogenous Estrogen Metabolites for Human Estrogen Receptor α and β Subtypes: Insights into the Structural Determinants Favoring a Differential Subtype Binding

et al. 2006

View full text Add to dashboard Cite

To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) alpha or beta subtype and also to gain insights into the structural determinants favoring differential subtype binding, we studied the binding affinities of 74 natural or synthetic estrogens, including more than 50 steroidal analogs of estradiol-17beta (E2) and estrone (E1) for human ER alpha and ER beta. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ER alpha and ER beta, but some of them retained differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16 alpha-hydroxyestradiol (estriol), 16 beta-hydroxyestradiol-17 alpha, and 16-ketoestrone, had distinct preferential binding affinity for human ER beta over ER alpha (difference up to 18-fold). Notably, although E2 has nearly the highest and equal binding affinity for ER alpha and ER beta, E1 and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ER alpha over ER beta, whereas 16 alpha-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ER beta over ER alpha. Hence, facile metabolic conversion of parent hormone E2 to various metabolites under different physiological conditions may serve unique functions by providing differential activation of the ER alpha or ER beta signaling system. Lastly, our computational three-dimensional quantitative structure-activity relationship/comparative molecular field analysis of 47 steroidal estrogen analogs for human ER alpha and ER beta yielded useful information on the structural features that determine the preferential activation of the ER alpha and ER beta subtypes, which may aid in the rational design of selective ligands for each human ER subtype.

show abstract

Section: D-ring Derivativessupporting

confidence: 86%

Quantitative Structure-Activity Relationship of Various Endogenous Estrogen Metabolites for Human Estrogen Receptor α and β Subtypes: Insights into the Structural Determinants Favoring a Differential Subtype Binding

et al. 2006

View full text Add to dashboard Cite

show abstract

“…The extent of steric shielding of the 17P-hydroxyl group of synthetic steroid oestrogens by substituents at the 17a-position correlates with their variety of abilities to elicit the oestrogenic response. 25 Studies on the 0-H stretching band in their infrared spectra, and of the O H signal in the lH n.m.r. spectrum in [2H6]dimethyl sulphoxide, lead to the conclusion that a 17aethyl group, in particular, inhibits hydrogen-bonding interactions between the steroid and its receptor by blocking approach to lone-pairs of electrons on oxygen, whereas 17aethynyl groups, at the other extreme, leave hydrogen-bonding unimpaired and allow high biological Molecularmechanics calculations concerning conformations of the 17ethyl side-chain have confirmed this conclusion.…”

Section: Receptor Binding Of Steroidsmentioning

confidence: 99%