Artículo

Rodriguez, C.R.; Alvarez, L.D.; Dansey, M.V.; Paolo, L.S.; Veleiro, A.S.; Pecci, A.; Burton, G. "Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity" (2017) Journal of Steroid Biochemistry and Molecular Biology. 165:268-276
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Abstract:

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

Registro:

Documento: Artículo
Título:Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity
Autor:Rodriguez, C.R.; Alvarez, L.D.; Dansey, M.V.; Paolo, L.S.; Veleiro, A.S.; Pecci, A.; Burton, G.
Filiación:Universidad de Buenos Aires, CONICET. UMYMFOR and Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Pabellón 2, Ciudad UniversitariaBuenos Aires C1428EGA, Argentina
Universidad de Buenos Aires, CONICET. IFIBYNE and Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Pabellón 2, Ciudad UniversitariaBuenos Aires C1428EGA, Argentina
Palabras clave: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
Año:2017
Volumen:165
Página de inicio:268
Página de fin:276
DOI: http://dx.doi.org/10.1016/j.jsbmb.2016.07.001
Título revista:Journal of Steroid Biochemistry and Molecular Biology
Título revista abreviado:J. Steroid Biochem. Mol. Biol.
ISSN:09600760
CODEN:JSBBE
CAS:fluoroacetic acid, 144-49-0; histidine, 645-35-2, 7006-35-1, 71-00-1; hydrogen, 12385-13-6, 1333-74-0; tryptophan, 6912-86-3, 73-22-3; 3 [3 [[2 chloro 3 (trifluoromethyl)benzyl](2 diphenylethyl)amino]propoxy]phenylacetic acid, 405911-09-3; cholesterol, 57-88-5; fluorine, 7782-41-4; 25,25-difluoro-27-nor-26-hydroxycholesterol; 25,25-difluoro-27-norcholestenoic acid; Alcohols; Benzoates; Benzylamines; Cholestenes; cholestenoic acid; Cholesterol; Fluorine; GW 3965; Hydroxycholesterols; Ligands; Liver X Receptors; Norsteroids; Oxysterols
Registro:http://digital.bl.fcen.uba.ar/collection/paper/document/paper_09600760_v165_n_p268_Rodriguez

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Citas:

---------- APA ----------
Rodriguez, C.R., Alvarez, L.D., Dansey, M.V., Paolo, L.S., Veleiro, A.S., Pecci, A. & Burton, G. (2017) . Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity. Journal of Steroid Biochemistry and Molecular Biology, 165, 268-276.
http://dx.doi.org/10.1016/j.jsbmb.2016.07.001
---------- CHICAGO ----------
Rodriguez, C.R., Alvarez, L.D., Dansey, M.V., Paolo, L.S., Veleiro, A.S., Pecci, A., et al. "Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity" . Journal of Steroid Biochemistry and Molecular Biology 165 (2017) : 268-276.
http://dx.doi.org/10.1016/j.jsbmb.2016.07.001
---------- MLA ----------
Rodriguez, C.R., Alvarez, L.D., Dansey, M.V., Paolo, L.S., Veleiro, A.S., Pecci, A., et al. "Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity" . Journal of Steroid Biochemistry and Molecular Biology, vol. 165, 2017, pp. 268-276.
http://dx.doi.org/10.1016/j.jsbmb.2016.07.001
---------- VANCOUVER ----------
Rodriguez, C.R., Alvarez, L.D., Dansey, M.V., Paolo, L.S., Veleiro, A.S., Pecci, A., et al. Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity. J. Steroid Biochem. Mol. Biol. 2017;165:268-276.
http://dx.doi.org/10.1016/j.jsbmb.2016.07.001