Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity
Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites o...
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2017
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v165_n_p268_Rodriguez http://hdl.handle.net/20.500.12110/paper_09600760_v165_n_p268_Rodriguez |
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paper:paper_09600760_v165_n_p268_Rodriguez |
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dspace |
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Universidad de Buenos Aires |
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I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Cholestenoic acid Liver X receptor Molecular dynamics Oxysterols 25,25 difluoro 27 norcholest 5 ene 3beta,26 diol 25,25 difluoro 27 norcholestenoic acid 25,25 difluoroacid 27 norcholestenoic acid alcohol derivative aldehyde ethyl bromodifluoroacetate fluoroacetic acid histidine hydrogen liver X receptor liver X receptor beta oxysterol tryptophan unclassified drug 25,25-difluoro-27-nor-26-hydroxycholesterol 25,25-difluoro-27-norcholestenoic acid 3 [3 [[2 chloro 3 (trifluoromethyl)benzyl](2 diphenylethyl)amino]propoxy]phenylacetic acid benzoic acid derivative benzylamine derivative cholestane derivative cholestenoic acid cholesterol cholesterol derivative fluorine ligand liver X receptor norsteroid oxysterol protein binding Article conformational transition deoxygenation expression vector fluorination HEK293 cell line human human cell hydrogen bond irradiation ligand binding luciferase assay molecular dynamics molecular interaction molecular model Reformatsky reaction synthesis ultrasound agonists antagonists and inhibitors chemistry nuclear magnetic resonance spectroscopy signal transduction tissue distribution Alcohols Benzoates Benzylamines Cholestenes Cholesterol Fluorine HEK293 Cells Humans Hydrogen Bonding Hydroxycholesterols Ligands Liver X Receptors Magnetic Resonance Spectroscopy Molecular Dynamics Simulation Norsteroids Oxysterols Protein Binding Signal Transduction Tissue Distribution |
| spellingShingle |
Cholestenoic acid Liver X receptor Molecular dynamics Oxysterols 25,25 difluoro 27 norcholest 5 ene 3beta,26 diol 25,25 difluoro 27 norcholestenoic acid 25,25 difluoroacid 27 norcholestenoic acid alcohol derivative aldehyde ethyl bromodifluoroacetate fluoroacetic acid histidine hydrogen liver X receptor liver X receptor beta oxysterol tryptophan unclassified drug 25,25-difluoro-27-nor-26-hydroxycholesterol 25,25-difluoro-27-norcholestenoic acid 3 [3 [[2 chloro 3 (trifluoromethyl)benzyl](2 diphenylethyl)amino]propoxy]phenylacetic acid benzoic acid derivative benzylamine derivative cholestane derivative cholestenoic acid cholesterol cholesterol derivative fluorine ligand liver X receptor norsteroid oxysterol protein binding Article conformational transition deoxygenation expression vector fluorination HEK293 cell line human human cell hydrogen bond irradiation ligand binding luciferase assay molecular dynamics molecular interaction molecular model Reformatsky reaction synthesis ultrasound agonists antagonists and inhibitors chemistry nuclear magnetic resonance spectroscopy signal transduction tissue distribution Alcohols Benzoates Benzylamines Cholestenes Cholesterol Fluorine HEK293 Cells Humans Hydrogen Bonding Hydroxycholesterols Ligands Liver X Receptors Magnetic Resonance Spectroscopy Molecular Dynamics Simulation Norsteroids Oxysterols Protein Binding Signal Transduction Tissue Distribution Dansey, Maria Virginia Veleiro, Adriana Silvia Pecci, Adali Burton, Gerardo Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity |
| topic_facet |
Cholestenoic acid Liver X receptor Molecular dynamics Oxysterols 25,25 difluoro 27 norcholest 5 ene 3beta,26 diol 25,25 difluoro 27 norcholestenoic acid 25,25 difluoroacid 27 norcholestenoic acid alcohol derivative aldehyde ethyl bromodifluoroacetate fluoroacetic acid histidine hydrogen liver X receptor liver X receptor beta oxysterol tryptophan unclassified drug 25,25-difluoro-27-nor-26-hydroxycholesterol 25,25-difluoro-27-norcholestenoic acid 3 [3 [[2 chloro 3 (trifluoromethyl)benzyl](2 diphenylethyl)amino]propoxy]phenylacetic acid benzoic acid derivative benzylamine derivative cholestane derivative cholestenoic acid cholesterol cholesterol derivative fluorine ligand liver X receptor norsteroid oxysterol protein binding Article conformational transition deoxygenation expression vector fluorination HEK293 cell line human human cell hydrogen bond irradiation ligand binding luciferase assay molecular dynamics molecular interaction molecular model Reformatsky reaction synthesis ultrasound agonists antagonists and inhibitors chemistry nuclear magnetic resonance spectroscopy signal transduction tissue distribution Alcohols Benzoates Benzylamines Cholestenes Cholesterol Fluorine HEK293 Cells Humans Hydrogen Bonding Hydroxycholesterols Ligands Liver X Receptors Magnetic Resonance Spectroscopy Molecular Dynamics Simulation Norsteroids Oxysterols Protein Binding Signal Transduction Tissue Distribution |
| description |
Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11-H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor-steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293 T cells co-transfected with full length human LXRβ expression vector. The 25,25-difluoro-27-norcholestenoic acid was an inverse agonist and antagonist similar to its non-fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5-ene-3β,26-diol was an agonist. Molecular dynamics simulation of the ligand-receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the case of the difluoroalcohol, the fluorine atoms actively participated in the interaction with several residues in the ligand binding pocket leading to a stabilization of the active receptor conformation. © 2016 Elsevier Ltd |
| author |
Dansey, Maria Virginia Veleiro, Adriana Silvia Pecci, Adali Burton, Gerardo |
| author_facet |
Dansey, Maria Virginia Veleiro, Adriana Silvia Pecci, Adali Burton, Gerardo |
| author_sort |
Dansey, Maria Virginia |
| title |
Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity |
| title_short |
Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity |
| title_full |
Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity |
| title_fullStr |
Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity |
| title_full_unstemmed |
Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity |
| title_sort |
fluorinated oxysterol analogues: synthesis, molecular modelling and lxrβ activity |
| publishDate |
2017 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v165_n_p268_Rodriguez http://hdl.handle.net/20.500.12110/paper_09600760_v165_n_p268_Rodriguez |
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AT danseymariavirginia fluorinatedoxysterolanaloguessynthesismolecularmodellingandlxrbactivity AT veleiroadrianasilvia fluorinatedoxysterolanaloguessynthesismolecularmodellingandlxrbactivity AT pecciadali fluorinatedoxysterolanaloguessynthesismolecularmodellingandlxrbactivity AT burtongerardo fluorinatedoxysterolanaloguessynthesismolecularmodellingandlxrbactivity |
| _version_ |
1768541619926073344 |
| spelling |
paper:paper_09600760_v165_n_p268_Rodriguez2023-06-08T15:57:21Z Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity Dansey, Maria Virginia Veleiro, Adriana Silvia Pecci, Adali Burton, Gerardo Cholestenoic acid Liver X receptor Molecular dynamics Oxysterols 25,25 difluoro 27 norcholest 5 ene 3beta,26 diol 25,25 difluoro 27 norcholestenoic acid 25,25 difluoroacid 27 norcholestenoic acid alcohol derivative aldehyde ethyl bromodifluoroacetate fluoroacetic acid histidine hydrogen liver X receptor liver X receptor beta oxysterol tryptophan unclassified drug 25,25-difluoro-27-nor-26-hydroxycholesterol 25,25-difluoro-27-norcholestenoic acid 3 [3 [[2 chloro 3 (trifluoromethyl)benzyl](2 diphenylethyl)amino]propoxy]phenylacetic acid benzoic acid derivative benzylamine derivative cholestane derivative cholestenoic acid cholesterol cholesterol derivative fluorine ligand liver X receptor norsteroid oxysterol protein binding Article conformational transition deoxygenation expression vector fluorination HEK293 cell line human human cell hydrogen bond irradiation ligand binding luciferase assay molecular dynamics molecular interaction molecular model Reformatsky reaction synthesis ultrasound agonists antagonists and inhibitors chemistry nuclear magnetic resonance spectroscopy signal transduction tissue distribution Alcohols Benzoates Benzylamines Cholestenes Cholesterol Fluorine HEK293 Cells Humans Hydrogen Bonding Hydroxycholesterols Ligands Liver X Receptors Magnetic Resonance Spectroscopy Molecular Dynamics Simulation Norsteroids Oxysterols Protein Binding Signal Transduction Tissue Distribution Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11-H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor-steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293 T cells co-transfected with full length human LXRβ expression vector. The 25,25-difluoro-27-norcholestenoic acid was an inverse agonist and antagonist similar to its non-fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5-ene-3β,26-diol was an agonist. Molecular dynamics simulation of the ligand-receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the case of the difluoroalcohol, the fluorine atoms actively participated in the interaction with several residues in the ligand binding pocket leading to a stabilization of the active receptor conformation. © 2016 Elsevier Ltd Fil:Dansey, M.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2017 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v165_n_p268_Rodriguez http://hdl.handle.net/20.500.12110/paper_09600760_v165_n_p268_Rodriguez |