5,6,11,12-Tetrahydrochrysenes: synthesis of rigid stilbene systems designed to be fluorescent ligands for the estrogen receptor

Hwang, Kwang Jin; O’Neil, James P.; Katzenellenbogen, John A.

doi:10.1021/jo00030a039

Cited by 41 publications

(53 citation statements)

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“…The ER hormone-binding domains were expressed in Escherichia coli in a pET15b vector, using standard methods (Novagen) (12) and purified by batchwise adsorption onto a nickel resin, according to the manufacturers suggestions (Qiagen). HBDs were diluted to 6 nM in TG buffer and incubated for 60 min at 0°C with 2 nM tetrahydrochrysene (THC)-nitrile (24,25), or no ligand for background. The free THC-nitrile was not removed since under these conditions nearly all of the ligand is bound.…”

Section: Methodsmentioning

confidence: 99%

“…1) (24), that have excellent fluorescent properties and have been used to assay the binding of ligands to ER and the distribution of the receptor in cells (25,29). An unusual characteristic of these fluorescent estrogens is that they emit at longer wavelengths when bound (wild type ER) ϭ 0.11 nM; EC 50 E2 (E353Q ER) ϭ 1.0 nM.…”

Section: Selection Of Sites In the Estrogen Receptor Likely To Determmentioning

confidence: 99%

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Determinants of Ligand Specificity of Estrogen Receptor-α: Estrogen versus Androgen Discrimination

Ekena

Katzenellenbogen

1998

Journal of Biological Chemistry

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We have been interested in understanding how the estrogen receptor (ER) binds estrogens and discriminates between different classes of steroids with closely related structures. Using insights from our prior studies on ER and from sequence comparisons of steroid receptors, we identified three residues in the hormone-binding domain of the human ER, Leu 345 , Thr 347 , and Glu 353 , that we considered were likely to be involved in steroid A-ring recognition and therefore estrogen versus androgen discrimination. We then tested the effect on ER activity of mutating these ER residues to the corresponding androgen receptor residues. Specifically, we examined the ability of the mutant receptors to bind and be activated by 17␤-estradiol and three different androgens. No change in receptor activity was observed with the T347N mutation, while the L345S mutation greatly reduced ER activity in response to all ligands. Interestingly, the E353Q substitution behaved as expected, causing a 9-fold reduction in the transactivation potency of estradiol and a concomitant 10 -140-fold increase in the transactivation potency of different androgens. These reciprocal changes in the transcriptional effectiveness of estrogens and androgens correlated with a decreased affinity of the E353Q ER for estradiol binding and an increased affinity for androgen binding. Therefore, amino acid Glu 353 appears to be playing a significant role in binding the A-ring phenolic group of estradiol and in receptor discrimination between estrogens and the most closely structurally related steroids, androgens. Based on this data and our earlier observations, we propose a model for the orientation of ligand within the binding pocket of ER in which the A-ring 3-phenol of estradiol is hydrogen bonded to Glu 353 in helix-3 and the 17␤-hydroxyl of estradiol is hydrogen bonded to His 524 in helix-11. Our findings with estrogen and androgen suggest that this orientation of the steroid in the ligandbinding pocket, with the steroid A-ring in contact with helix-3 and the D-ring in contact with helix-11 residues, is likely to be general for all the steroid hormone receptors.The distinctive biological effects of the different classes of steroid hormones were recognized early in this century, when the basic physiology of the endocrine system was being elucidated. Despite their overall structural similarity, each class of steroid hormones does have characteristic structural features. In this regard, the estrogens (C 18 steroids) have a characteristic aromatic A-ring with a phenolic hydroxyl at C-3, which uniquely distinguish them from the other four steroid classes, androgens, progestins, glucocorticoids, and mineralocorticoids, all of which are 3-keto steroids. Among the latter, the structural differences are principally in their C-and D-rings. The androgens (C 19 steroids) are identical to the estrogens in this region, whereas the progestins and corticosteroids (C 21 steroids) all have distinctive hydroxylation and/or oxidation patterns in their C-and D-rings.The steroid ...

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Section: Methodsmentioning

confidence: 99%

Section: Selection Of Sites In the Estrogen Receptor Likely To Determmentioning

confidence: 99%

Determinants of Ligand Specificity of Estrogen Receptor-α: Estrogen versus Androgen Discrimination

Ekena

Katzenellenbogen

1998

Journal of Biological Chemistry

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“…Calf serum was from Hyclone Laboratories, Inc. (Logan, UT) and FCS was from Atlanta Biologicals (Atlanta, GA). The synthesis of compound 2 has been described (8,9). The expression vector for human ER␣ (pCMV5-hER) was constructed previously as described (5).…”

Section: Chemicals Materials and Plasmid Constructionsmentioning

confidence: 99%

Novel Ligands that Function as Selective Estrogens or Antiestrogens for Estrogen Receptor-α or Estrogen Receptor-β*

et al. 1999

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We report on the identification of novel, nonsteroidal ligands that show pronounced subtype-selective differences in ligand binding and transcriptional potency or efficacy for the two estrogen receptor (ER) subtypes, ER alpha and ER beta. An aryl-substituted pyrazole is an ER alpha potency-selective agonist, showing higher binding affinity for ER alpha and 120-fold higher potency in stimulation of ER alpha vs. ER beta in transactivation assays in cells. A tetrahydrochrysene (THC) has a 4-fold preferential binding affinity for ER beta; it is an agonist on ER alpha, but a complete antagonist on ER beta. Intriguingly, the antagonist activity of THC is associated with the R,R-enantiomer (R,R-THC). The S,S-enantiomer (S,S-THC) is an agonist on both ER alpha and ER beta but has a 20-fold lower affinity for ER beta than R,R-THC. This difference in binding affinity accounts for the full ER beta antagonist activity of the THC racemate (a 1:1 mixture of R,R-THC and S,S-THC). These compounds should be useful in probing the conformational changes in these two ERs that are evoked by agonists and antagonists, and in evaluating the distinct roles that ER beta and ER alpha may play in the diverse target tissues in which estrogens act.

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“…To a solution of phenol 16 (390.7 mg, 1.1334 mmol) and 2,6-lutidine (316.9 µL, 2.72 mmol) in CH 2 Cl 2 (30 mL) at 0 ºC, was added trifluoromethane sulfonic anhydride (767.5 mg, 2.72 mmol). 12 The solution was stirred at 0 ºC for 20 min, followed by 1 h at 25 ºC. Further reaction time did not result in more than 67% conversion, so the solution was poured into water, extracted with CH 2 Cl 2 , then with EtOAc.…”

Section: -(6-methoxy-2-(4-methoxyphenyl)-1h-inden-3-yl)phenyl Triflumentioning

confidence: 99%

Differential Response of Estrogen Receptor Subtypes to 1,3-Diarylindene and 2,3-Diarylindene Ligands

et al. 2005

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Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERalpha and ERbeta in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERalpha and ERbeta subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERalpha, while antagonizing estradiol action at ERbeta.

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5,6,11,12-Tetrahydrochrysenes: synthesis of rigid stilbene systems designed to be fluorescent ligands for the estrogen receptor

Cited by 41 publications

References 1 publication

Determinants of Ligand Specificity of Estrogen Receptor-α: Estrogen versus Androgen Discrimination

Determinants of Ligand Specificity of Estrogen Receptor-α: Estrogen versus Androgen Discrimination

Novel Ligands that Function as Selective Estrogens or Antiestrogens for Estrogen Receptor-α or Estrogen Receptor-β*

Differential Response of Estrogen Receptor Subtypes to 1,3-Diarylindene and 2,3-Diarylindene Ligands

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