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Abstract:

The introduction of a hemisuccinate group at the 21-position of the passive antiglucocorticoid 21OH-6,19OP leads to a compound (21HS-6,19OP) with a notable activity profile toward the glucocorticoid receptor (GR). In contrast to the parent steroid, 21HS-6,19OP behaves as a pure agonist of GR activity in direct transactivation assays. However, the apoptotic effects of 21HS-6,19OP show that the effect depends on cell type: while 21HS-6,19OP is a pure agonist in L929 mouse fibroblasts, in thymocytes 21HS-6,19OP had significant antiglucocorticoid activity. This tissue-specific activity makes 21HS-6,19OP a novel selective GR modulator. To investigate the molecular basis of action of 21HS-6,19OP, we carried out molecular dynamics simulations (6 ns) of the GR ligand binding domain (LBD) complexed with 21HS-6,19OP. Our results indicate that the hemisuccinate moiety may play a key role in stabilizing the active conformation of the receptor dimerization interface, reverting the changes observed with the antagonist 21OH-6,19OP. Other changes in regions of the GR related to cofactor recruitment (possibly tissue-specific), could explain this particular activity profile. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

Registro:

Documento: Artículo
Título:Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor
Autor:Álvarez, L.D.; Martí, M.A.; Veleiro, A.S.; Misico, R.I.; Estrin, D.A.; Pecci, A.; Burton, G.
Filiación:Departamento de Química Orgánica, UMYMFOR-CONICET, Pabellón 2, C1428EGA Buenos Aires, Argentina
Departamento de Química Inorgánica Analítica Y Química Física, INQUIMAE-CONICET, Universidad de Buenos Aires, Argentina
Departamento de Química Biológica, IFIBYNE-CONICET, Universidad de Buenos Aires, Argentina
Palabras clave:Apoptosis; Glucocorticoid receptors; Molecular dynamics; Structure-activity relationships; Tissue-specific activity; 21 hydroxy 6,19 oxidoprogesterone; 21 succinyloxy 6,19 epoxyprogesterone; 21-hydroxy-6,19-oxidoprogesterone; 21-succinyloxy-6,19-epoxyprogesterone; drug derivative; gestagen; glucocorticoid receptor; progesterone; animal; apoptosis; article; cell strain COS1; Cercopithecus; chemistry; computer simulation; dimerization; drug potentiation; human; mouse; reporter gene; structure activity relation; Animals; Apoptosis; Cercopithecus aethiops; Computer Simulation; COS Cells; Dimerization; Genes, Reporter; Humans; Mice; Progesterone; Progestins; Receptors, Glucocorticoid; Structure-Activity Relationship
Año:2008
Volumen:3
Número:12
Página de inicio:1869
Página de fin:1877
DOI: http://dx.doi.org/10.1002/cmdc.200800256
Título revista:ChemMedChem
Título revista abreviado:ChemMedChem
ISSN:18607179
CAS:progesterone, 57-83-0; 21-hydroxy-6,19-oxidoprogesterone; 21-succinyloxy-6,19-epoxyprogesterone; Progesterone, 57-83-0; Progestins; Receptors, Glucocorticoid
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_18607179_v3_n12_p1869_Alvarez

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Citas:

---------- APA ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Misico, R.I., Estrin, D.A., Pecci, A. & Burton, G. (2008) . Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor. ChemMedChem, 3(12), 1869-1877.
http://dx.doi.org/10.1002/cmdc.200800256
---------- CHICAGO ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Misico, R.I., Estrin, D.A., Pecci, A., et al. "Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor" . ChemMedChem 3, no. 12 (2008) : 1869-1877.
http://dx.doi.org/10.1002/cmdc.200800256
---------- MLA ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Misico, R.I., Estrin, D.A., Pecci, A., et al. "Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor" . ChemMedChem, vol. 3, no. 12, 2008, pp. 1869-1877.
http://dx.doi.org/10.1002/cmdc.200800256
---------- VANCOUVER ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Misico, R.I., Estrin, D.A., Pecci, A., et al. Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor. ChemMedChem. 2008;3(12):1869-1877.
http://dx.doi.org/10.1002/cmdc.200800256