Quantitative structure-activity relationships of estrogenic steroids substituted at C14, C15

Abstract

The uterotropic activity of thirty 3-methoxyestradiol derivatives is measured and discussed on the basis of X-ray crystallographic results and quantitative structure-activity relationship analyses involving hydrophobic substituent constants π and f as well as steric parameters Pr and L. in addition, estrogenicity is compared to data of interceptive activity and receptor binding affinity. All the biological data exhibit a high degree of intercorrelation. 17β-Hydroxysteroids having 14α configuration reveal a generally better capability of high-affinity binding than those being 14β configurated. Between the uterotropic activity and the hydrophobicity of C14, C15 substituents, statistically significant correlations are found which suggest a close contact between the steroidal d-ring subsite and the receptor protein (e.g. for 14α steroids: log UDD = −0.996π −0.392; n = 9, r = −0.943, i = 0.235, ( = −7.5, α < 0.001). The hydrophobic nature of both 14α and 14β medium-sized substituents employed is shown by QSAR regressions to exert a stronger influence than steric effects. Furthermore, there are indications to additional hydrogen bonding and steric repulsion phenomena. As to the receptor-binding models discussed in the literature, it is concluded that the receptor protein has a high conformational flexibility to accommodate very different drug structures all having the common phenolic ring A. But, if an appropriate spacing of steroidal key atoms is recognized by the receptor and, consequently, the steroid-receptor complex is formed, the binding is complemented by hydrophobic interactions also in the d-ring region.