Studies on Structure Activity Relationships

Several studies have been carried out on the relationship between the structure of compounds and their estrogen-like activity (12,19). Although it is expected that the binding affinity of the ligand to the ER does not accurately indicate the biological activity of the ligand in vivo, receptor binding is still a requisite for the stimulation of biological activity. Wiese et al. (20) evaluated 42 analogs of estradiol for their ER-binding affinity and toxicity to breast cancer cell lines, correlating the structure of these compounds with the above activities by means of three-dimensional quantitative structure activity (QSAR), employing a comparative molecular field analysis (CoMFA). They concluded that additional structural characteristics to those responsible for tight receptor binding must be present to induce an optimal mitogenic response, such as steric factor interference in specific zones and electronegative and electropositive properties near position 3. Sadler et al. (21) used the CoMFA method, which can visualize the steric and electrostatic features of the ligands corresponding to ER-binding affinity. Using the above technique, 30 compounds sharing the transstilbene structure were examined and results were compared to information from the ER-binding affinities of substituted estradiol analogs. This study demonstrated the importance of hydroxy substituents in nonsteroidal ligands that mimic the 3-OH and 17-OH of estradiol to obtain a high binding affinity. Grese et al. (22) examined a series of raloxifene analogs in vitro and in vivo in which the 2-arylbenzothiophene substructure had been modified, measuring the reduction of serum cholesterol, uterine weight gain, and uterine eosinophil peroxidase activity in an ovariectomized (OVX) rat model. In this study, they showed the importance of highly electronegative 4'-substituents, such as hydroxy or fluoro attached to the raloxifene molecule, in their ability to bind to the receptor. They also showed that increasing steric bulk at position 4' led to increased uterine stimulation in vivo and that additional substitutions at the 4-, 5-, or 7-positions of the benzothiophene moiety resulted in reduced biological activity, while an additional substitution of the 2-aryl moiety had little effect.

Shiau et al. (23) investigated the crystal structure of the human LBD complex with an agonist (diethylstilbestrol), together with a peptide derived from an ERa coactivator and the crystal structure of LBD with an antagonist (4-hydroxy tamoxifen). They showed that the peptide binds as a short a helix to a hydrophobic groove on the LBD surface in the complex with the agonist, while the binding of the antagonist promotes a helix 12 conformation, inhibiting the binding of a coactivator. They concluded that two effects occur when the antagonist binds to LBD: a change in the position of the helix 12 so that it occupies part of the coactivator-binding groove, and a change in LBD conformation resulting from the interaction with the antagonist that stabilizes this conformation. These data suggest that the ligand structure will have a direct effect on the complex ER-ligand structure, which dictates the specific biological activities. Thus a search for natural and synthetic ligands that form complexes leading to tissue-specific beneficial effects is desired.

Figure 1 Structures of several phytoestrogens, tamoxifen, raloxifene, and estradiol.
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