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John A Katzenellenbogen - One of the best experts on this subject based on the ideXlab platform.
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synthesis and evaluation of estrogen receptor ligands with bridged oxabicyclic cores containing a diarylethylene motif estrogen antagonists of unusual structure
Journal of Medicinal Chemistry, 2005Co-Authors: Haibing Zhou, Benita S. Katzenellenbogen, Fabio Stossi, John S Comninos, John A KatzenellenbogenAbstract:A new series of ligands for the estrogen receptor (ER) based on a three-dimensional structural motif consisting of a bridged oxabicyclic core (7-oxabicyclo[2.2.1]heptene or heptadiene) were synthesized and examined for their receptor binding activity and as regulators of transcription through the two ER subtypes, ER alpha and ER beta. The prototypical ligands also contain a 1,2-diarylethylene motif, common to many Nonsteroidal estrogens, as an embellishment on the oxabicyclic core. Thus, these ligands bear peripheral groups typically found in ER ligands, built here upon an overall three-dimensional core topology that is unusual for these targets. Most of these compounds were conveniently synthesized by a Diels-Alder reaction of various 3,4-diarylfurans with a variety of dienophiles, neat and under mild conditions in the absence of catalysts. Some of the synthesized compounds display good binding affinity for the ER, and in transcription assays, the highest affinity compounds are antagonists on both ERs. Molecular modeling studies suggest a structural basis for the antagonist activity of these compounds. These compounds, based on the bicyclo[2.2.1]core system, expand the structural diversity of ligands that can be antagonists for the estrogen receptors.
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novel structural templates for estrogen receptor ligands and prospects for combinatorial synthesis of estrogens
Chemistry & Biology, 1999Co-Authors: Brian E Fink, Deborah S Mortensen, Shaun R Stauffer, Zachary D Aron, John A KatzenellenbogenAbstract:Introduction The development of estrogen pharmaceutical agents with appropriate tissue-selectivity profiles has not yet benefited substantially from the application of combinatorial synthetic approaches to the preparation of structural classes that are known to be ligands for the estrogen receptor (ER). We have developed an estrogen pharmacophore that consists of a simple heterocyclic core scaffold, amenable to construction by combinatorial methods, onto which are appended 3–4 peripheral substituents that embody substructural motifs commonly found in Nonsteroidal estrogens. The issue addressed here is whether these heterocyclic core structures can be used to prepare ligands with good affinity for the ER. Results We prepared representative members of various azole core structures. Although members of the imidazole, thiazole or isoxazole classes generally have weak binding for the ER, several members of the pyrazole class show good binding affinity. The high-affinity pyrazoles bear close conformational relationship to the Nonsteroidal ligand raloxifene, and they can be fitted into the ligand-binding pocket of the ER-raloxifene X-ray structure. Conclusions Compounds such as these pyrazoles, which are novel ER ligands, are well suited for combinatorial synthesis using solid-phase methods.
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Nonsteroidal estrogens bearing acyl azide functions potential electrophilic and photoaffinity labeling agents for the estrogen receptor
Steroids, 1992Co-Authors: Kevin G Pinney, Kathryn E Carlson, John A KatzenellenbogenAbstract:Abstract In an effort to develop novel affinity labeling agents for the estrogen receptor, we have synthesized two Nonsteroidal ligands, a 1-aroyl-2-aryl tetralin system (1) and a 2-aryl-3-aroylbenzo[b]thiophene system (2). These agents, patterned after the Lilly antiestrogens trioxifene and L Y 117018, respectively, embody acyl azide functions as part of a benzoyl chromophore. The acyl azide group has weak acylating activity, suitable for electrophilic affinity labeling, but this function is also photoreactive and, in its particular embodiment within these ligands, it could provide an efficient photochemical route to the highly reactive singlet acyl nitrene. The tetralin system (1) was prepared in nine steps from 6-methoxy-1-tetralone, and the benzothiophene system (2) was prepared in four steps from a known substituted benzo[b]thiophene precursor. In competitive binding assays, both compounds show reasonable binding affinity for the rat and lamb uterine estrogen receptor: estradiol = 100%, 1 = 3%, and 2 = 12%. When assayed by indirect receptor consumption assays, both compounds appear to have substantial capacity for irreversible binding (electrophilic reaction) with the receptor. This reactivity, which suggests that acylation of the receptor has occurred, is photoreversible. The nature of this ligand-receptor interaction is being investigated further.
Živković Lada - One of the best experts on this subject based on the ideXlab platform.
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Dry olive leaf extract attenuates DNA damage induced by estradiol and diethylstilbestrol in human peripheral blood cells in vitro
'Elsevier BV', 2019Co-Authors: Topalović Dijana, Dekanski Dragana, Potparević Biljana, Pirković Andrea, Borozan Sunčica, Bajić Vladan, Stojanović Danilo, Giampieri Francesca, Gasparrini Massimiliano, Živković LadaAbstract:Phenolic groups of steroidal or Nonsteroidal estrogens can redox cycle, leading to oxidative stress, where creation of reactive oxygen species are recognized as the main mechanism of their DNA damage properties. Dry olive (Olea europaea L.) leaf extract is known to contain bioactive and antioxidative components and to have an ability to modulate the effects of various oxidants in cells. The main goal of this study was to investigate antigenotoxic potential of a standardized dry olive leaf extract on DNA damage induced by 17β-estradiol and diethylstilbestrol in human whole blood cells in vitro, using comet assay. Our results indicated that both hormones showed a genotoxic effect at a concentration of 100 μM (P lt 0.05, n = 6). Dry olive leaf extract was efficient in reducing number of cells with estrogen-induced DNA damage at tested concentrations (0.125, 0.5 and 1 mg/mL) (P lt 0.05, n = 6) and under two experimental protocols, pre-treatment and post-treatment, exhibiting antigenotoxic properties. Analysis of antioxidant properties of the extract revealed moderate ABTS radical scavenging properties and reducing power. Overall, our results suggested that the protective potential of dry olive leaf extract could arise from the synergistic effect of its scavenging activity and enhancement of the cells' antioxidant capacity
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Dry olive leaf extract attenuates DNA damage induced by estradiol and diethylstilbestrol in human peripheral blood cells in vitro
'Elsevier BV', 2019Co-Authors: Topalović Dijana, Dekanski Dragana, Pirković Andrea, Borozan Sunčica, Bajić Vladan, Stojanović Danilo, Giampieri Francesca, Gasparrini Massimiliano, Spremo-potparević Biljana, Živković LadaAbstract:Phenolic groups of steroidal or Nonsteroidal estrogens can redox cycle, leading to oxidative stress, where creation of reactive oxygen species are recognized as the main mechanism of their DNA damage properties. Dry olive (Olea europaea L.) leaf extract is known to contain bioactive and antioxidative components and to have an ability to modulate the effects of various oxidants in cells. The main goal of this study was to investigate antigenotoxic potential of a standardized dry olive leaf extract on DNA damage induced by 17 beta-estradiol and diethylstilbestrol in human whole blood cells in vitro, using comet assay. Our results indicated that both hormones showed a genotoxic effect at a concentration of 100 mu M (P < 0.05, n = 6). Dry olive leaf extract was efficient in reducing number of cells with estrogen-induced DNA damage at tested concentrations (0.125, 0.5 and 1 mg/mL) (P < 0.05, n = 6) and under two experimental protocols, pre-treatment and post-treatment, exhibiting antigenotoxic properties. Analysis of antioxidant properties of the extract revealed moderate ABTS radical scavenging properties and reducing power. Overall, our results suggested that the protective potential of dry olive leaf extract could arise from the synergistic effect of its scavenging activity and enhancement of the cells antioxidant capacity
Haibing Zhou - One of the best experts on this subject based on the ideXlab platform.
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elemental isomerism a boron nitrogen surrogate for a carbon carbon double bond increases the chemical diversity of estrogen receptor ligands
Chemistry & Biology, 2007Co-Authors: Haibing Zhou, Benita S. Katzenellenbogen, Kathryn E Carlson, Kendall W Nettles, John B Bruning, Younchang Kim, Andrzej Joachimiak, Sanjay Sharma, Fabio Stossi, Geoffrey L GreeneAbstract:Summary To increase the chemical diversity of bioactive molecules by incorporating unusual elements, we have examined the replacement of a C=C double bond with the isoelectronic, isostructural B-N bond in the context of Nonsteroidal estrogen receptor (ER) ligands. While the B-N bond was hydrolytically labile in the unhindered cyclofenil system, the more hindered anilino dimesitylboranes, analogs of triarylethylene estrogens, were easily prepared, hydrolytically stable, and demonstrated substantial affinity for ERs. X-ray analysis of one ERα-ligand complex revealed steric clashes with the para methyl groups distorting the receptor; removal of these groups resulted in an increase in affinity, potency, and transcriptional efficacy. These studies define the structural determinants of stability and cellular bioactivity of a B-N for C=C substitution in Nonsteroidal estrogens and provide a framework for further exploration of "elemental isomerism" for diversification of drug-like molecules.
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synthesis and evaluation of estrogen receptor ligands with bridged oxabicyclic cores containing a diarylethylene motif estrogen antagonists of unusual structure
Journal of Medicinal Chemistry, 2005Co-Authors: Haibing Zhou, Benita S. Katzenellenbogen, Fabio Stossi, John S Comninos, John A KatzenellenbogenAbstract:A new series of ligands for the estrogen receptor (ER) based on a three-dimensional structural motif consisting of a bridged oxabicyclic core (7-oxabicyclo[2.2.1]heptene or heptadiene) were synthesized and examined for their receptor binding activity and as regulators of transcription through the two ER subtypes, ER alpha and ER beta. The prototypical ligands also contain a 1,2-diarylethylene motif, common to many Nonsteroidal estrogens, as an embellishment on the oxabicyclic core. Thus, these ligands bear peripheral groups typically found in ER ligands, built here upon an overall three-dimensional core topology that is unusual for these targets. Most of these compounds were conveniently synthesized by a Diels-Alder reaction of various 3,4-diarylfurans with a variety of dienophiles, neat and under mild conditions in the absence of catalysts. Some of the synthesized compounds display good binding affinity for the ER, and in transcription assays, the highest affinity compounds are antagonists on both ERs. Molecular modeling studies suggest a structural basis for the antagonist activity of these compounds. These compounds, based on the bicyclo[2.2.1]core system, expand the structural diversity of ligands that can be antagonists for the estrogen receptors.
Topalović Dijana - One of the best experts on this subject based on the ideXlab platform.
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Dry olive leaf extract attenuates DNA damage induced by estradiol and diethylstilbestrol in human peripheral blood cells in vitro
'Elsevier BV', 2019Co-Authors: Topalović Dijana, Dekanski Dragana, Potparević Biljana, Pirković Andrea, Borozan Sunčica, Bajić Vladan, Stojanović Danilo, Giampieri Francesca, Gasparrini Massimiliano, Živković LadaAbstract:Phenolic groups of steroidal or Nonsteroidal estrogens can redox cycle, leading to oxidative stress, where creation of reactive oxygen species are recognized as the main mechanism of their DNA damage properties. Dry olive (Olea europaea L.) leaf extract is known to contain bioactive and antioxidative components and to have an ability to modulate the effects of various oxidants in cells. The main goal of this study was to investigate antigenotoxic potential of a standardized dry olive leaf extract on DNA damage induced by 17β-estradiol and diethylstilbestrol in human whole blood cells in vitro, using comet assay. Our results indicated that both hormones showed a genotoxic effect at a concentration of 100 μM (P lt 0.05, n = 6). Dry olive leaf extract was efficient in reducing number of cells with estrogen-induced DNA damage at tested concentrations (0.125, 0.5 and 1 mg/mL) (P lt 0.05, n = 6) and under two experimental protocols, pre-treatment and post-treatment, exhibiting antigenotoxic properties. Analysis of antioxidant properties of the extract revealed moderate ABTS radical scavenging properties and reducing power. Overall, our results suggested that the protective potential of dry olive leaf extract could arise from the synergistic effect of its scavenging activity and enhancement of the cells' antioxidant capacity
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Dry olive leaf extract attenuates DNA damage induced by estradiol and diethylstilbestrol in human peripheral blood cells in vitro
'Elsevier BV', 2019Co-Authors: Topalović Dijana, Dekanski Dragana, Pirković Andrea, Borozan Sunčica, Bajić Vladan, Stojanović Danilo, Giampieri Francesca, Gasparrini Massimiliano, Spremo-potparević Biljana, Živković LadaAbstract:Phenolic groups of steroidal or Nonsteroidal estrogens can redox cycle, leading to oxidative stress, where creation of reactive oxygen species are recognized as the main mechanism of their DNA damage properties. Dry olive (Olea europaea L.) leaf extract is known to contain bioactive and antioxidative components and to have an ability to modulate the effects of various oxidants in cells. The main goal of this study was to investigate antigenotoxic potential of a standardized dry olive leaf extract on DNA damage induced by 17 beta-estradiol and diethylstilbestrol in human whole blood cells in vitro, using comet assay. Our results indicated that both hormones showed a genotoxic effect at a concentration of 100 mu M (P < 0.05, n = 6). Dry olive leaf extract was efficient in reducing number of cells with estrogen-induced DNA damage at tested concentrations (0.125, 0.5 and 1 mg/mL) (P < 0.05, n = 6) and under two experimental protocols, pre-treatment and post-treatment, exhibiting antigenotoxic properties. Analysis of antioxidant properties of the extract revealed moderate ABTS radical scavenging properties and reducing power. Overall, our results suggested that the protective potential of dry olive leaf extract could arise from the synergistic effect of its scavenging activity and enhancement of the cells antioxidant capacity
Barry R. Goldin - One of the best experts on this subject based on the ideXlab platform.
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Nonsteroidal estrogens and estrogen antagonists: mechanism of action and health implications.
Journal of the National Cancer Institute, 1994Co-Authors: Barry R. GoldinAbstract:Endogenous estrogens comprise a family of compounds that have a polycyclic structure and contain a steroid nucleus. These compounds exhibit a wide diversity of biochemical and biological activities. estrogens both induce and stimulate the cellular proliferation and differentiation of specific cell types in target tissues, a prime example being the critical role of these hormones in sexual differentiation and reproduction. estrogens also exert a critical role in body fat deposition and in preventing bone resorption in the maintenance of bone structure. Given that these compounds exert such a wide range of activities without requiring absolute structural specificity and that there are in existence a tremendous number of related naturally occurring and synthetic polycyclic compounds, it is highly likely that compounds other than endogenous steroidal estrogens will possess at least some estrogenic properties. This, in fact, is the case. Many of these compounds have been found to inhibit the action of endogenous mammalian steroidal estrogens. Compounds exhibiting this inhibitory activity have been called antiestrogens. Although the terms antiestrogen and antiestrogenic are now widely used in the literature, they do not accurately reflect or describe the properties of these compounds. Antiestrogens, in the strict sense of the word, should be substances that in and of themselves exhibit biological properties opposite to those of estrogens. Typically, what is actually measured is the ability of these substances to inhibit estrogen activity in the presence of estrogens. Therefore the terms estrogen antagonist or estrogen inhibitor would more correctly describe this biological activity. The inhibitory effect is analogous to that which is observed for enzyme inhibitors that, as a result of some structural similarity to natural substrates, are bound and acted upon by the relevant enzymes, and even if the degree of catalysis is low, the net result is that the activity of the enzyme on the natural substrate(s) is inhibited. In this issue of the Journal, Liu et al. (7) report on the estrogenic and estrogen inhibitory properties of indolo[3,2b]carbazole (ICZ), an acid-derived condensation product of indole-3-carbinol (I3C). I3C is a naturally occurring compound found in vegetables such as cabbage, broccoli, Brussels sprouts, and cauliflower. ICZ was found to induce CYP1A1, a member of the cytochrome P450 family, in the MCF-7 mammary tumor cell line. These findings are similar to those reported from the same laboratory for 3-methylcholanthrene (MC) and 2,3,7,8-tetrachlorodibenzo-/?-dioxin (TCDD) (2,3). In separate assays, ICZ was also found to stimulate the proliferation of MCF-7 cells and the incorporation of [ 3H]thymidine into DNA, similar to that observed for estradiol (E2) but to lesser extents and with higher molar concentrations required to mediate the effects. Similar findings were reported for the induction of procathepsin D and for chloramphenicol acetyl transferase (CAT) activity. Both E2 and ICZ separately increased the secretion of procathepsin D in MCF-7 cells and the CAT reporter gene activity in MCF-7 cells transiently transfected with an estrogen-resp onsive vit-CAT plasmid. When cells were exposed to both compounds at the same time, the levels of activity measured in both of the above assays were reduced as compared with those obtained in parallel from cells treated with E2 alone, thus demonstrating by independent assays the estrogen inhibitory effects of ICZ. ICZ was also shown to decrease the number of occupied estrogen receptors (ERs) and to compete with E2 for binding to ER, although this binding was very weak; the IC50 (concentration that causes 50% inhibition of growth) was 23 \iM, compared with 0.063 [iM for tamoxifen. It has been previously shown that I3C, ICZ, MC, and TCDD bind to the aryl hydrocarbon (Ah) receptor and are considered Ah receptor agonists (4-6). Liu et al. conclude that the induction of CYP1A1 gene expression is not the primary factor in the inhibitory estrogenic properties of ICZ, since the ICZ inhibition is seen at lower concentrations and after a shorter amount of time than is required for CYP1A1 induction. The suggestion that ICZ can inhibit estrogen activity via induction of the cytochrome P450 monoxygenase system comes from studies showing that TCDD and I3C increase CYPlA2-catalyzed 2hydroxylation of estradiol and, as a consequence, decrease the estrogen response (7). Liu et al. (7) propose that Ah receptor agonists act antagonistically toward estrogens by an as-yet-unknown cellular signal transduction interaction between the Ah
