Stabilization of estradiol-receptor complexes by elimination of cytosolic factors

Fishman, Jerry H.

doi:10.1016/0006-291x(83)91019-7

Cited by 16 publications

(6 citation statements)

References 9 publications

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“…The homogenate was then centrifuged at 100000g, 4 °C. The cytosol thus isolated was pretreated with dextran coated charcoal (DCC on ice) 45 and reisolated using centrifugation, before freezing at -20 °C for later use. The protein concentration of cytosol samples was determined using a standard Bradford protein assay and an appropriate protein concentration range (150 µg protein in a total volume of 0.14 mL) for assay prepared.…”

Section: -Benzyl-1-phenyl-1-[4-(morpholinylethoxy)phenyl]but-1-ene (2ementioning

confidence: 99%

“…3,[6][7][8][9] The chemotherapeutic and antiestrogenic potential of the compounds prepared is determined through appropriate biochemical assays. [14][15][16][17][18] The availability of highly resolved crystal structure studies of the estrogen receptor R (ERR) allows the investigation of both actual and theoretical interactions of both estrogenic and antiestrogenic materials in the LBD. [10][11][12] A thorough computational investigation of the predicted orientation and interaction of representative compounds within the LBD of the human ERR is undertaken, with a view to rationalizing antiestrogenic activity observed through analyzing ligand-receptor interactions, to provide an insight into the basis for biological activity of the compounds prepared.…”

Section: Introductionmentioning

confidence: 99%

“…It has been suggested that building flexibility into the rigid backbone of antiestrogens could enhance their activity and binding affinity for the estrogen receptor ,− The chemotherapeutic and antiestrogenic potential of the compounds prepared is determined through appropriate biochemical assays. − The availability of highly resolved crystal structure studies of the estrogen receptor α (ERα) allows the investigation of both actual and theoretical interactions of both estrogenic and antiestrogenic materials in the LBD. − A thorough computational investigation of the predicted orientation and interaction of representative compounds within the LBD of the human ERα is undertaken, with a view to rationalizing antiestrogenic activity observed through analyzing ligand−receptor interactions, to provide an insight into the basis for biological activity of the compounds prepared . Such work further illustrates the eclectic liganding behavior of ERα and its tolerance for flexible antiestrogen systems.…”

Section: Introductionmentioning

confidence: 99%

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Flexible Estrogen Receptor Modulators: Design, Synthesis, and Antagonistic Effects in Human MCF-7 Breast Cancer Cells

et al. 2001

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Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds' potential interactions with specific residues within the human estrogen receptor alpha ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.

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Section: -Benzyl-1-phenyl-1-[4-(morpholinylethoxy)phenyl]but-1-ene (2ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Flexible Estrogen Receptor Modulators: Design, Synthesis, and Antagonistic Effects in Human MCF-7 Breast Cancer Cells

et al. 2001

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“…To confirm our hypothesis that these compounds were acting through the estrogen receptor, an initial binding investigation ,, was carried out using compounds 7 and 15 as representative candidates. The study indicates the compounds are competitive antagonists with moderate binding affinity for the ER (binding K i 3.2 ± 2.1 μM ( 7 ) and 828 ± 106 nM ( 15 )), marginally weaker than that measured for tamoxifen ( 1 ) and the structurally related benzocycloheptenes .…”

mentioning

confidence: 99%

Benzoxepin-Derived Estrogen Receptor Modulators: A Novel Molecular Scaffold for the Estrogen Receptor

et al. 2004

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We present and examine the efficacy of a novel benzoxepin-based scaffold for modulation of the human estrogen receptor. Receptor tolerance of this new molecular scaffold is examined through presentation of experimentally determined antiproliferative effects on human MCF-7 breast tumor cells and measured binding affinities. The effect of functional group substitution on the benzoxepin scaffold is explored through a brief computational structure-activity relationship investigation with molecular simulation.

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“…Although displacement of [3H]oestradiol from its nuclear receptor is limited at low temperature (Love, Cowan, Laing & Leake, 1983), Peck & Clark (1977) gave indications that the dissociation of oestradiol receptor could be promoted in salt-containing buffers by exposure to DCC. More recently, Fishman (1983) reported that DCC could neutralize, in uterine cytosol, factors that are responsible for thermolability of oestradiol receptors.…”

Section: Introductionmentioning

confidence: 98%

A novel class of inactive steroid-binding sites in female rat liver nuclei

Béchet¹,

Perry²

1986

Journal of Endocrinology

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Nuclear salt extracts from intact female rat liver showed insignificant levels of progesterone-, oestradiol-, testosterone- or dexamethasone-specific binding. However, brief exposure of nuclear extracts to dextran-coated charcoal (DCC) induced binding for all the above classes of steroids. This 'DCC-effect', which was reproduced neither by gel filtration nor by extensive dialysis of the nuclear extract, could not be ascribed to removal of endogenous free or loosely bound steroids. We show that rat liver nuclei contain a class of secondary binding sites (BSII), which exhibit moderate or low affinity for steroid ligands, positive co-operativity, and cross-reaction between classes of steroids. The capacity of BSII sites to bind steroids depends strictly on prior neutralization by DCC of endogenous heat-stable non-dialysable inhibitor(s). The putative roles of these BSII binding sites are discussed in relation to component(s) probably responsible for inhibitory activity.

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Stabilization of estradiol-receptor complexes by elimination of cytosolic factors

Cited by 16 publications

References 9 publications

Flexible Estrogen Receptor Modulators: Design, Synthesis, and Antagonistic Effects in Human MCF-7 Breast Cancer Cells

Flexible Estrogen Receptor Modulators: Design, Synthesis, and Antagonistic Effects in Human MCF-7 Breast Cancer Cells

Benzoxepin-Derived Estrogen Receptor Modulators: A Novel Molecular Scaffold for the Estrogen Receptor

A novel class of inactive steroid-binding sites in female rat liver nuclei

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