Œstrogenic Activity of Alkylated Stilœstrols

Dodds, E. C.; Golberg, L.; Lawson, W.; Robinson, Robert

doi:10.1038/142034a0

Cited by 83 publications

(41 citation statements)

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“…At this time, Dodds reported (12) that diethyl substitution at the ethylenic bond of stilbestrol ( Fig. 2) produces an extremely potent estrogen (12,13); other substitutions produce less active compounds (14). The structural similarity between diethylstilbestrol and estradiol (the formula was established by 1938) was noted (12), but an attempt to mimic the rigid steroid structure by the synthesis of dihydroxyhexahydrochrysene (Fig.…”

Section: Historical Perspective: the First 25 Yearsmentioning

confidence: 99%

Structure-Activity Relationships of Estrogens

Jordan¹,

Mittal²,

Gosden³

et al. 1985

Environmental Health Perspectives

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The last 50 years has seen an exponential rise in the published reports about estrogen action. The model to describe the early events in the mechanism of action of estrogens via the estrogen receptor is updated in this paper to incorporate some of the recent data on the subcellular localization of the receptor. New evidence suggests that the receptor is a nuclear protein, so it appears that estrogens must first diffuse into the nuclear compartment to initiate estrogen action via the receptor complex. This review traces the development of potent estrogenic compounds by the study of their structure-activity relationships. Studies of structure-activity relationships in vivo using Allen Doisy or 3-day uterine weight tests can provide much valuable information, but the assays suffer from the complex problems of pharmacokinetics and metabolic transformation. Studies in vitro using primary cultures of rat pituitary or uterine cells to assay the ability of a compound to induce prolactin synthesis or progesterone receptor synthesis, respectively, can provide essential information about the structural requirements for a compound to produce estrogenic effects. Nevertheless, it should be pointed out that studies in vivo are required to determine whether a compound is metabolically activated to an estrogen. Estrogen receptor binding models are presented to describe the changes in a molecule that will predict high affinity for the ligand and agonist, partial agonist and antagonist properties of the ligand-receptor complex. Most estrogenic pesticides and phytoestrogens comform to the predictions of the estrogen receptor binding model.

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Section: Historical Perspective: the First 25 Yearsmentioning

confidence: 99%

Structure-Activity Relationships of Estrogens

Jordan¹,

Mittal²,

Gosden³

et al. 1985

Environmental Health Perspectives

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“…SARs for estrogens date back more than six decades to the early work of Dodds et al (4,5). The succeeding two decades saw the discovery of nonsteroidal estrogens, such as DES, based on understanding of the important structural features governing potency for steroidal estrogens.…”

Section: Introductionmentioning

confidence: 99%

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

Fang

Tong

Shi

et al. 2001

Chem. Res. Toxicol.

421

357

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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.

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“…This pharmacophore for ACAT inhibition is the diphenylethane (DPE) moiety of Sah 58-035. It has been known since the pioneering work of Dodds et al (1938), showing that diethylstilbestrol (DES) acts as a potent estrogen, that the DPE moiety could mimic the hexahydrophenanthrene motif of 17␤-estradiol (E 2 ). This observation led to the subsequent development of DPE derivatives that were at the origin of nonsteroidal estrogens and antiestrogens (Anstead et al, 1997;Jordan, 2003a).…”

mentioning

confidence: 99%

The Prototypical Inhibitor of Cholesterol Esterification, Sah 58-035 [3-[Decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide], Is an Agonist of Estrogen Receptors

Médina¹,

Boubekeur²,

Balaguer³

et al. 2006

J Pharmacol Exp Ther

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We have shown recently that estrogen receptor (ER) ligands share a diphenyl ethane pharmacophore with Sah 58-035 [3- [decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide], a prototypical inhibitor of the acyl-cholesterolacyl-transferase (ACAT), which enabled us to establish that ER ligands were potent inhibitors of ACAT and blocked the formation of foam cells. In the present study, we have tested whether this structural similarity means that Sah 58-035 is an ER modulator. We report that Sah 58-035 bound to ER␣ and ER␤ with an IC 50 of 2.9 and 3.1 M, respectively. Docking studies using molecular modeling of Sah 58-035 with the X-ray structure of the ER showed that Sah 58-035 fits well into the ligand binding site known for 4-hydroxy-tamoxifen. Despite having high threedimensional structural similarities with the pure antiestrogen ICI 164,384 [(N-n-butyl-N-methyl-11-[3,17␤-di-hydroxyestra-1,3, 5(10)-trien-7␣-yl]-undecanamide], we showed that Sah 58-035 is an agonist of ER for transcription and cellular proliferation. These data showed that Sah 58-035 was an estrogen receptor agonist and that the size and the chemical nature of the side chain were critical for agonist versus antagonist activity on ER. This new molecular mechanism of action for Sah 58-035 has to be taken into account in understanding better its pharmacological activities. Moreover, these data give new structural insights into the understanding of agonist versus antagonist activities of ER ligands and also for the conception of new drugs with a dual ACAT inhibition and ER modulation potential and their evaluation in different pathologies where both targets are involved, such as atherosclerosis, Alzheimer's disease, and cancer.We have reported recently that the prototypical acyl-cholesterol-acyl-transferase (ACAT) inhibitor Sah 58-035 and estrogen receptor (ER) ligands shared a common pharmacophore that caused the ER ligands to inhibit ACAT (de Medina et al., 2004b), a new important target for the antiestrogen tamoxifen that may explain its antiatherogenicity in mammals. This pharmacophore for ACAT inhibition is the diphenylethane (DPE) moiety of Sah 58-035. It has been known since the pioneering work of Dodds et al. (1938), showing that diethylstilbestrol (DES) acts as a potent estrogen, that the DPE moiety could mimic the hexahydrophenanthrene motif of 17␤-estradiol (E 2 ). This observation led to the subsequent development of DPE derivatives that were at the origin of nonsteroidal estrogens and antiestrogens (Anstead et al., 1997;Jordan, 2003a). Crystallographic analysis of E 2 -S.S.-P. is in charge of research for the Centre National de la Recherche Scientifique.

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Œstrogenic Activity of Alkylated Stilœstrols

Cited by 83 publications

References 1 publication

Structure-Activity Relationships of Estrogens

Structure-Activity Relationships of Estrogens

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

The Prototypical Inhibitor of Cholesterol Esterification, Sah 58-035 [3-[Decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide], Is an Agonist of Estrogen Receptors

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