2018
Pěnčíková, Kateřina; Brenerová, Petra; Svržková, Lucie; Hrubá, Eva; Pálková, Lenka; Vondráček, Jan; Lehmler, Hans-Joachim; Machala, Miroslav
Atropisomers of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro. Journal Article
In: Environmental science and pollution research international, vol. 25, no. 17, pp. 16411–16419, 2018, ISSN: 1614-7499 0944-1344, (Place: Germany).
Abstract | Links | BibTeX | Tags: Androgen receptor, Animals, Atropisomer, Biotransformation, Chiral, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/*chemistry/metabolism, Estrogen receptors, Humans, Polychlorinated biphenyl, Polychlorinated Biphenyls/*chemistry, Pregnane X receptor, Receptors, Stereoisomerism, Steroid/chemistry/metabolism
@article{pencikova_atropisomers_2018,
title = {Atropisomers of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro.},
author = {Kateřina Pěnčíková and Petra Brenerová and Lucie Svržková and Eva Hrubá and Lenka Pálková and Jan Vondráček and Hans-Joachim Lehmler and Miroslav Machala},
doi = {10.1007/s11356-017-0683-x},
issn = {1614-7499 0944-1344},
year = {2018},
date = {2018-06-01},
journal = {Environmental science and pollution research international},
volume = {25},
number = {17},
pages = {16411–16419},
abstract = {PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.},
note = {Place: Germany},
keywords = {Androgen receptor, Animals, Atropisomer, Biotransformation, Chiral, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/*chemistry/metabolism, Estrogen receptors, Humans, Polychlorinated biphenyl, Polychlorinated Biphenyls/*chemistry, Pregnane X receptor, Receptors, Stereoisomerism, Steroid/chemistry/metabolism},
pubstate = {published},
tppubtype = {article}
}
PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.
2017
Maier, Lukáš; Khirsariya, Prashant; Hylse, Ondřej; Adla, Santosh Kumar; Černová, Lenka; Poljak, Michal; Krajčovičová, Soňa; Weis, Erik; Drápela, Stanislav; Souček, Karel; Paruch, Kamil
Diastereoselective Flexible Synthesis of Carbocyclic C-Nucleosides. Journal Article
In: The Journal of organic chemistry, vol. 82, no. 7, pp. 3382–3402, 2017, ISSN: 1520-6904 0022-3263, (Place: United States).
Abstract | Links | BibTeX | Tags: Cell Proliferation/drug effects, Cells, Cultured, Cyclopentanes/chemical synthesis/chemistry/*pharmacology, Humans, Molecular Structure, Nucleosides/chemical synthesis/chemistry/*pharmacology, Stereoisomerism
@article{maier_diastereoselective_2017,
title = {Diastereoselective Flexible Synthesis of Carbocyclic C-Nucleosides.},
author = {Lukáš Maier and Prashant Khirsariya and Ondřej Hylse and Santosh Kumar Adla and Lenka Černová and Michal Poljak and Soňa Krajčovičová and Erik Weis and Stanislav Drápela and Karel Souček and Kamil Paruch},
doi = {10.1021/acs.joc.6b02594},
issn = {1520-6904 0022-3263},
year = {2017},
date = {2017-04-01},
journal = {The Journal of organic chemistry},
volume = {82},
number = {7},
pages = {3382–3402},
abstract = {Carbocyclic C-nucleosides are quite rare. Our route enables flexible preparation of three classes of these nucleoside analogs from common precursors-properly substituted cyclopentanones, which can be prepared racemic (in six steps) or optically pure (in ten steps) from inexpensive norbornadiene. The methodology allows flexible manipulation of individual positions around the cyclopentane ring, namely highly diastereoselective installation of carbo- and heterocyclic substituents at position 1', orthogonal functionalization of position 5', and efficient inversion of stereochemistry at position 2'. Newly prepared carbocyclic C-analog of tubercidine, profiled in MCF7 (breast cancer) and HFF1 (human foreskin fibroblasts) cell cultures, is less potent than tubercidine itself, but more selectively toxic toward the tumorigenic cells.},
note = {Place: United States},
keywords = {Cell Proliferation/drug effects, Cells, Cultured, Cyclopentanes/chemical synthesis/chemistry/*pharmacology, Humans, Molecular Structure, Nucleosides/chemical synthesis/chemistry/*pharmacology, Stereoisomerism},
pubstate = {published},
tppubtype = {article}
}
Carbocyclic C-nucleosides are quite rare. Our route enables flexible preparation of three classes of these nucleoside analogs from common precursors-properly substituted cyclopentanones, which can be prepared racemic (in six steps) or optically pure (in ten steps) from inexpensive norbornadiene. The methodology allows flexible manipulation of individual positions around the cyclopentane ring, namely highly diastereoselective installation of carbo- and heterocyclic substituents at position 1', orthogonal functionalization of position 5', and efficient inversion of stereochemistry at position 2'. Newly prepared carbocyclic C-analog of tubercidine, profiled in MCF7 (breast cancer) and HFF1 (human foreskin fibroblasts) cell cultures, is less potent than tubercidine itself, but more selectively toxic toward the tumorigenic cells.
2005
Plísková, Martina; Vondrácek, Jan; Kren, Vladimír; Gazák, Radek; Sedmera, Petr; Walterová, Daniela; Psotová, Jitka; Simánek, Vilím; Machala, Miroslav
Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation. Journal Article
In: Toxicology, vol. 215, no. 1-2, pp. 80–89, 2005, ISSN: 0300-483X, (Place: Ireland).
Abstract | Links | BibTeX | Tags: Animals, Aryl Hydrocarbon/*metabolism, Cell Line, Cell Survival/drug effects, Dose-Response Relationship, Drug, Estrogen/*metabolism, Humans, Luciferases/biosynthesis/genetics, Molecular Structure, Rats, Receptors, Silybin, Silymarin/chemistry/pharmacology, Stereoisomerism, Tumor
@article{pliskova_effects_2005,
title = {Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation.},
author = {Martina Plísková and Jan Vondrácek and Vladimír Kren and Radek Gazák and Petr Sedmera and Daniela Walterová and Jitka Psotová and Vilím Simánek and Miroslav Machala},
doi = {10.1016/j.tox.2005.06.020},
issn = {0300-483X},
year = {2005},
date = {2005-11-01},
journal = {Toxicology},
volume = {215},
number = {1-2},
pages = {80–89},
abstract = {Silymarin, a standardized mixture of flavonolignans, or its major constituents could be effective for prevention and treatment of hepatic damage or skin cancer. However, their potential side effects, such as modulation of endocrine functions via the disruption of estrogen receptor (ER) and/or aryl hydrocarbon receptor (AhR) activation, are largely unknown. In the present study, we investigated impact of silymarin, its constituents and a series of their synthetic derivatives on ER- and AhR-mediated activities using in vitro reporter gene assays. We found that none of the compounds under study affected the AhR-mediated activity in rat hepatoma cells. Contrary to that, several compounds behaved as either partial or full ER agonists. Silymarin elicited partial ER activation, with silybin B being probably responsible for a majority of the weak ER-mediated activity of silymarin; silybin A and other flavonolignans were found to be inactive and potent ER agonist taxifolin is only a minor constituent of silymarin. To our knowledge, this is probably the first time, when receptor-specific in vitro effects of separated diastereomers have been demonstrated. In contrast to silymarin constituents, the synthetic silybin derivatives, potentially useful as chemoprotective agents, did not modulate the ER-mediated activity, with exception of 23-O-pivaloylsilybin. Interestingly, 7-O-benzylsilybin potentiated ER-mediated activity of 17beta-estradiol despite possessing no estrogenic activity. In conclusion, our data suggest that estrogenicity of some silymarin constituents should be taken in account as their potential side effect when considered as chemopreventive compounds. These results also stress the need to study biological activities of purified or synthesized diastereomers of silybin derivatives.},
note = {Place: Ireland},
keywords = {Animals, Aryl Hydrocarbon/*metabolism, Cell Line, Cell Survival/drug effects, Dose-Response Relationship, Drug, Estrogen/*metabolism, Humans, Luciferases/biosynthesis/genetics, Molecular Structure, Rats, Receptors, Silybin, Silymarin/chemistry/pharmacology, Stereoisomerism, Tumor},
pubstate = {published},
tppubtype = {article}
}
Silymarin, a standardized mixture of flavonolignans, or its major constituents could be effective for prevention and treatment of hepatic damage or skin cancer. However, their potential side effects, such as modulation of endocrine functions via the disruption of estrogen receptor (ER) and/or aryl hydrocarbon receptor (AhR) activation, are largely unknown. In the present study, we investigated impact of silymarin, its constituents and a series of their synthetic derivatives on ER- and AhR-mediated activities using in vitro reporter gene assays. We found that none of the compounds under study affected the AhR-mediated activity in rat hepatoma cells. Contrary to that, several compounds behaved as either partial or full ER agonists. Silymarin elicited partial ER activation, with silybin B being probably responsible for a majority of the weak ER-mediated activity of silymarin; silybin A and other flavonolignans were found to be inactive and potent ER agonist taxifolin is only a minor constituent of silymarin. To our knowledge, this is probably the first time, when receptor-specific in vitro effects of separated diastereomers have been demonstrated. In contrast to silymarin constituents, the synthetic silybin derivatives, potentially useful as chemoprotective agents, did not modulate the ER-mediated activity, with exception of 23-O-pivaloylsilybin. Interestingly, 7-O-benzylsilybin potentiated ER-mediated activity of 17beta-estradiol despite possessing no estrogenic activity. In conclusion, our data suggest that estrogenicity of some silymarin constituents should be taken in account as their potential side effect when considered as chemopreventive compounds. These results also stress the need to study biological activities of purified or synthesized diastereomers of silybin derivatives.