Structure−Activity Relationships for a Large Diverse Set of Natural, Synthetic, and Environmental Estrogens

Abstract

Understanding structural requirements for a chemical to exhibit estrogen receptor (ER) binding has been important in various fields. This knowledge has been directly and indirectly applied to design drugs for human estrogen replacement therapy, and to identify estrogenic endocrine disruptors. This paper reports structure-activity relationships (SARs) based on a total of 230 chemicals, including both natural and xenoestrogens. Activities were generated using a validated ER competitive binding assay, which covers a 10 6 -fold range. This study is focused on identification of structural commonalities among diverse ER ligands. It provides an overall picture of how xenoestrogens structurally resemble endogenous 17 -estradiol (E 2 ) and the synthetic estrogen diethylstilbestrol (DES). On the basis of SAR analysis, five distinguishing criteria were found to be essential for xenoestrogen activity, using E 2 as a template: (1) H-bonding ability of the phenolic ring mimicking the 3-OH, (2) H-bond donor mimicking the17 -OH and O-O distance between 3-and 17 -OH, (3) precise steric hydrophobic centers mimicking steric 7R-and 11 -substituents, (4) hydrophobicity, and (5) a ring structure. The 3-position H-bonding ability of phenols is a significant requirement for ER binding. This contributes as both a H-bond donor and acceptor, although predominantly as a donor. However, the 17 -OH contributes as a H-bond donor only. The precise space (the size and orientation) of steric hydrophobic bulk groups is as important as a 17 -OH. Where a direct comparison can be made, strong estrogens tend to be more hydrophobic. A rigid ring structure favors ER binding. The knowledge derived from this study is rationalized into a set of hierarchical rules that will be useful in guidance for identification of potential estrogens.

Potential anti-inflammatory, anti-adhesive, anti/estrogenic, and angiotensin-converting enzyme inhibitory activities of anthocyanins and their gut metabolites

“…In a similar way, Chalopin et al (2010) showed that the endothelium-dependent vasorelaxation of delphinidin and a red wine extract is mediated via ERa. With respect to ERa, the presence of up to 2-OH groups in the B-ring of the molecular structure decreased the affinity of the anthocyanins to the ERa (Fang et al 2001). In contrast, delphinidin-3-glucoside and gallic acid with 3-OH groups demonstrated the highest affinity for ERb in our study.…”

A conformational study of hydroxyflavones by vibrational spectroscopy coupled to DFT calculations

“…A wide variety of pharmacologically relevant functions is assigned to these compounds [22], from antibacterial, antifungal, antiviral, anti-spasmolytic, estrogen-like, anti-inflammatory and anti-HIV to anticancer [23][24][25][26][27][28][29][30][31]. This group of compounds contains a common moiety -a chromone skeleton with a phenyl substituent in the pyrone ring ( Fig.…”

Interaction of organophosphate pesticides and related compounds with the androgen receptor.

“…Quantitative structure-activity relationship (QSAR) models and qualitative SAR approaches have had some success in identifying and depicting structural features that contribute to the ability of a chemical to interact with steroid hormones, for both the estrogen receptor (ER) (Anstead et al 1997;Fang et al 2001;McKinney and Waller 1994;Tong et al 1997aTong et al , 1997bTong et al , 1998Waller et al 1996b;Wiese and Brooks 1994) and the AR (Loughney and Schwender 1992;Mekenyan et al 1997;Singh et al 2000;Tucker et al 1988;Waller et al 1996a). In the case of environmentally occurring chemicals, studies have revealed a common pattern of steric and electronic features involved in molecular recognition and receptor binding affinity, in spite of the molecular diversity of such data sets.…”