2-Phenylindoles with sulfur containing side chains. Estrogen receptor affinity, antiestrogenic potency, and antitumor activity

Biberger, Christian; Angerer, Erwin von

doi:10.1016/0960-0760(96)00004-0

Cited by 32 publications

(24 citation statements)

References 26 publications

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“…Because both estrogen receptors and ACAT are potential targets for atherosclerosis, the answer then will come from in vivo studies in which the effect of selective ACAT inhibitors will be evaluated and compared with dual ER modulators and ACAT inhibitors. Dual modulators of ERs and inhibitors of ACAT may represent new compounds of high medical interest because they will target two impor- ICI 164,384, ICI 182,780, EM-319 (Jordan, 2003b), and ZK-164,015 (Biberger and von Angerer, 1996). The chemical groups involved in pure antagonist activity are highlighted in gray.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Relative binding affinities (RBA) were determined as described previously [32]. The 500 l incubation mixture comprised 5 nM [ 3 H] 17␤-estradiol (added in 100 l Tris-buffer (0.01 M, pH 7.5), supplemented with EDTA (0.01 M) and NaN 3 (0.003 M)), 10 −9 -10 −5 M competing ligand (in 100 l buffer), 100 l of calf uterine cytosol, and buffer.…”

Section: Estrogen Receptor Binding Assaymentioning

confidence: 99%

“…Since the antiestrogenic potency of steroidal and non-steroidal ligands of the ER benefits from a side chain of 10 or more atoms including a functional group such as sulfoxide [31], sulfone [32] or amide, it was reasonable to link the lipophilic element to the indole nitrogen which generally carries the side chain in indole-based antiestrogens. An alternative would be to modify one of the aromatic rings in the 2-phenylindole system to use it as carrier for the side chain.…”

Section: Introductionmentioning

confidence: 99%

2-Phenylindole sulfamates: inhibitors of steroid sulfatase with antiproliferative activity in MCF-7 breast cancer cells

Walter

Liebl

Angerer

2004

The Journal of Steroid Biochemistry and Molecular Biology

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“…We were able to demonstrate that non-steroidal antiestrogens of appropriate structure can be converted into estrone sulfatase inhibitors after modification of the phenolic hydroxy groups by sulfamoylation. An example for this type of inhibitors is 6, which derives from the pure antiestrogen ZK 164.015 [21]. An important finding of this earlier study was that the enzyme inhibitory activity of the 2-phenylindole derivatives increases in parallel to the estrogenic potency of the parent structure.…”

mentioning

confidence: 93%

Stilbene‐Based Inhibitors of Estrone Sulfatase with a Dual Mode of Action in Human Breast Cancer Cells

Walter

Liebl

Angerer

2004

Archiv der Pharmazie

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Estrone sulfate (E1S) is an endogenous prodrug that delivers estrone and, subsequently, estradiol to target cells, after hydrolysis by the enzyme estrone sulfatase, which is active in various tissues including hormone-dependent breast cancer. Blockade of this enzyme should reduce the estrogen level in breast cancer cells and prevent hormonal growth stimulation. In this study, a number of sulfamoyloxy-substituted stilbenes with side chains that guarantee antiestrogenic activity were synthesized and evaluated as inhibitors of estrone sulfatase. They inhibited this enzyme in human MDA-MB 231 breast cancer cells, with IC(50) values in the submicromolar range. The effects of both the free hydroxy derivatives and the sulfamates on gene activation were determined in transfected MCF-7/2a breast cancer cells stimulated either with estradiol or with estrone sulfate. The analysis of data revealed a dual mode of action of the majority of compounds. They blocked gene expression by inhibition of estrone sulfatase and by antiestrogenic action. This pharmacological profile was also observed in assays on antiproliferative activity. The most potent derivative 8 g inhibited the growth of wild-type human MCF-7 cells with an IC(50) value of 13 nM.

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2-Phenylindoles with sulfur containing side chains. Estrogen receptor affinity, antiestrogenic potency, and antitumor activity

Cited by 32 publications

References 26 publications

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

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

2-Phenylindole sulfamates: inhibitors of steroid sulfatase with antiproliferative activity in MCF-7 breast cancer cells

Stilbene‐Based Inhibitors of Estrone Sulfatase with a Dual Mode of Action in Human Breast Cancer Cells

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