Navegar

Colección

Datos Estadísticas

Artículo

Pecci, A.; Alvarez, L.D.; Veleiro, A.S.; Ceballos, N.R.; Lantos, C.P.; Burton, G. "New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects" (2009) Journal of Steroid Biochemistry and Molecular Biology. 113(3-5):155-162
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Antiglucocorticoids that act as antagonists at the glucocorticoid receptor (GR) level may be used to block or modulate the undesirable effects of glucocorticoid excess (from endogenous or exogenous origin). RU486 developed in the early 80s, is an antiglucocorticoid but also a potent antiprogestin and abortifacient, nevertheless it still remains as the only GR antagonist drug in the market. Further on, in view of the variety of physiological processes in which glucocorticoids are involved, selective antiglucocorticoids that can block only some of these processes (eventually with tissue specificity) would be highly desirable. The bridged pregnane 21-hydroxy-6,19-epoxyprogesterone, was developed as an alternative lead being an antagonist of the GR with no affinity for mineralocorticoid and progesterone receptors. Antagonistic activity was evidenced by partial blocking of dexamethasone induction of tyrosine aminotransferase (TAT) and thymocyte apoptosis. Replacement of the oxygen bridge by a sulfur bridge gave a less bent, more flexible molecule. 21-Hydroxy-6,19-epithioprogesterone exhibited improved antiapoptotic activity on thymocytes but was not effective blocking TAT induction. This selectivity was improved further by oxidation to the sulfone. The sulfone but not the reduced compound also reverted the dexamethasone-mediated inhibition of NFκB activity in HeLa cells. Blocking of the apoptotic effect of TNFα by dexamethasone in the L929 cell line (mouse fibroblasts), was only reverted partially by the sulfone which exhibited a mild agonistic/antagonistic activity in this assay. None of these compounds showed antiprogestin activity. Similar overall molecular shapes but more lipophylic and with higher metabolic stability were obtained by introduction of a methylene bridge (6,19-methanoprogesterone) or by a direct bond between C-6 and C-19 (6,19-cycloprogesterone and its 21-hydroxy derivative). The latter highly bent steroids showed affinity for the GR. Recently we performed molecular dynamics simulations of GR-ligand complexes to investigate the molecular basis of the passive antagonism exhibited by 21-hydroxy-6,19-epoxyprogesterone. On the basis of our findings, we proposed that the passive antagonist mode of action of this antiglucocorticoid analog resides, at least in part, in the incapacity of GR-21-hydroxy-6,19-epoxyprogesterone complex to dimerize, making the complex unable to activate gene transcription. © 2009 Elsevier Ltd. All rights reserved.

Registro:

Documento: Artículo
Título:New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects
Autor:Pecci, A.; Alvarez, L.D.; Veleiro, A.S.; Ceballos, N.R.; Lantos, C.P.; Burton, G.
Filiación:Departamento de Química Orgánica, UMYMFOR (CONICET-FCEN), Facultad de Ciencias Exactas y Naturales, Argentina
Departamento de Química Biológica (IFIBYNE-CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 2, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina
Palabras clave:21-hydroxy-6,19-epoxyprogesterone; 6,19-epithiopregnanes; Antiglucocorticoid; 21 hydroxy 6,19 epithioprogesterone; 21 hydroxy 6,19 epoxyprogesterone; 21 hydroxyepithiopregnane derivative; 6,19 cycloprogesterone; 6,19 epoxyprogesterone; 6,19 methanoprogesterone; abortive agent; antigestagen; bridged compound; carbene; carbon; dexamethasone; glucocorticoid; glucocorticoid antagonist; immunoglobulin enhancer binding protein; mifepristone; mineralocorticoid receptor; onapristone; oxygen; pregnane 21 hydroxy 6,19 epoxyprogesterone; progesterone; progesterone receptor; ru 43044; steroid; sulfone; sulfur; tumor necrosis factor alpha; tyrosine aminotransferase; unclassified drug; apoptosis; binding affinity; cell strain L 929; competitive inhibition; crystal structure; dimerization; dissociation constant; drug receptor binding; enzyme activation; enzyme inhibition; genetic transcription; HeLa cell; hormone inhibition; human; lipophilicity; molecular dynamics; nonhuman; oxidation; protein conformation; review; structure activity relation; thymocyte; transcription initiation; X ray diffraction; Animals; Dexamethasone; Glucocorticoids; Humans; Mifepristone; Models, Molecular; Molecular Conformation; Molecular Structure; Receptors, Glucocorticoid; Tumor Necrosis Factor-alpha; Tyrosine Transaminase
Año:2009
Volumen:113
Número:3-5
Página de inicio:155
Página de fin:162
DOI: http://dx.doi.org/10.1016/j.jsbmb.2008.12.018
Título revista:Journal of Steroid Biochemistry and Molecular Biology
Título revista abreviado:J. Steroid Biochem. Mol. Biol.
ISSN:09600760
CODEN:JSBBE
CAS:carbene, 2465-56-7; carbon, 7440-44-0; dexamethasone, 50-02-2; mifepristone, 84371-65-3; onapristone, 96346-61-1; oxygen, 7782-44-7; progesterone, 57-83-0; sulfone, 67015-63-8; sulfur, 13981-57-2, 7704-34-9; tyrosine aminotransferase, 9014-55-5; Dexamethasone, 50-02-2; Glucocorticoids; Mifepristone, 84371-65-3; Receptors, Glucocorticoid; Tumor Necrosis Factor-alpha; Tyrosine Transaminase, 2.6.1.5
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v113_n3-5_p155_Pecci

Referencias:

  • Jensen, E.V., Steroid hormone antagonists. Summary and future challenges (1995) Ann. N.Y. Acad. Sci., 761, pp. 1-4
  • Cadepond, F., Ulmann, A., Baulieu, E., RU-486 (mifepristone): mechanisms of action and clinical uses (1997) Annu. Rev. Med., 48, pp. 129-156
  • Nieman, L.K., Uses of RU 486 as an antiglucocorticoid (1993) Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assesing the Science and Recommending a Research Agenda, pp. 243-252. , Donaldson M.S., Dorllinger L., Brown S.S., and Benet L.Z. (Eds), National Academy Press, Washington, DC
  • Spitz, I.M., Bardin, C.W., Mifepristone (RU-486): a modulator of progestin and glucocorticoid action (1993) N. Engl. J. Med., 329, pp. 404-412
  • Kauppi, B., Jakob, C., Färnegárdh, M., Yang, J., Ahola, H., Alarcon, M., Calles, K., Carlquist, M., The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain (2003) J. Biol. Chem., 278, pp. 22748-22754
  • Zhang, J., Tsai, F.T., Geller, D.S., Differential interaction of RU486 with the progesterone and glucocorticoid receptors (2006) J. Mol. Endocrinol., 37, pp. 163-173
  • Moore, J.T., Collins, J.L., Pearce, K.H., The nuclear receptor superfamily and drug discovery (2006) ChemMedChem, 1, pp. 504-523
  • Teutsch, G., Gaillard-Moguilewsky, M., Lemoine, G., Nique, F., Philibert, D., Design of ligands for the glucocorticoid and progestin receptors (1991) Biochem. Soc. Trans., 19, pp. 901-908
  • Weeks, C.M., Duax, W.L., Wolff, M.E., Comparison of the molecular structure of six corticosteroids (1973) J. Am. Chem. Soc., 95, pp. 2865-2868
  • Burton, G., Galigniana, M.D., de Lavallaz, S., Brachet-Cota, A.L., Sproviero, E.M., Ghini, A.A., Lantos, C.P., Damasco, M.C., Sodium retaining activity of some natural and synthetic 21-deoxysteroids (1995) Mol. Pharmacol., 47, pp. 535-543
  • Veleiro, A.S., Pecci, A., Monteserín, M.C., Baggio, R.F., Garland, M.T., Lantos, C.P., Burton, G., 6,19-Sulfur-bridged progesterone analogues with antiimmunosuppressive activity (2005) J. Med. Chem., 48, pp. 5675-5683
  • Vicent, G.P., Monteserín, M.C., Veleiro, A.S., Burton, G., Lantos, C.P., Galigniana, M.D., 21-Hydroxy-6,19-oxidoprogesterone. A novel synthetic steroid with specific antiglucocorticoid properties in the rat (1997) Mol. Pharmacol., 52, pp. 749-753
  • Patel, F.A., Funder, J.W., Challis, J.R.G., Mechanism of cortisol/progesterone antagonism in the regulation of 15-hydroxyprostaglandin dehydrogenase activity and messenger ribonucleic acid levels in human chorion and placental trophoblast cells at term (2003) J. Clin. Endocrinol. Metab., 88, pp. 2922-2933
  • Honer, C., Nam, K., Fink, C., Marshall, P., Ksander, G., Chatelain, R.E., Cornell, W., Schumacher, C., Glucocorticoid receptor antagonism by cyproterone acetate and RU-486 (2003) Mol. Pharmacol., 63, pp. 1012-1020
  • Joselevich, M., Ghini, A.A., Burton, G., 6,19-Carbon-bridged steroids. Synthesis of 6,19-methanoprogesterone (2003) Org. Biomol. Chem., 1, pp. 939-943
  • Di Chenna, P.H., Veleiro, A.S., Sonego, J.M., Ceballos, N.R., Garland, M.T., Baggio, R.F., Burton, G., Synthesis of 6,19-cyclopregnanes. Constrained analogues of steroid hormones (2007) Org. Biomol. Chem., 5, pp. 2453-2457
  • Wagner, B.L., Pollio, G., Giangrande, P., Webster, J.C., Breslin, M., Mais, D.E., Cook, C.E., Mc-Donnell, D.P., The novel progesterone receptor antagonists RTI 3021-012 and RTI 3021-022 exhibit complex glucocorticoid receptor antagonist activities: implications for the development of dissociated antiprogestins (1999) Endocrinology, 140, pp. 1449-1458
  • Jantzen, H.M., Strähle, U., Gloss, B., Stewart, F., Scmidt, W., Boshart, M., Miksicek, R., Schütz, G., Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene (1987) Cell, 49, pp. 29-38
  • Wyllie, A.H., Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation (1980) Nature, 284, pp. 555-556
  • Cidlowski, J.A., King, K.L., Evans-Storms, R.B., Montague, J.W., Bortner, C.D., Hughes Jr., F.M., The biochemistry and molecular biology of glucocorticoid-induced apoptosis in the immune system (1996) Recent Prog. Horm. Res., 51, pp. 457-490
  • Fadok, V.A., Voelker, D.R., Campbell, P.A., Cohen, J.J., Bratton, D.L., Henson, P.M., Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages (1992) J. Immunol., 148, pp. 2207-2216
  • Boersma, A.W.M., Nooter, K., Oostrum, R.G., Stoter, G., Quantification of apoptotic cells with fluorescein isothiocyanate labeled annexin V in chinese hamster ovary cell cultures treated with cisplatin (1996) Cytometry, 24, pp. 123-130
  • Tuckermann, J.P., Kleiman, A., McPherson, K.G., Reichardt, H.M., Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis (2005) Crit. Rev. Cl. Lab. Sci., 42, pp. 71-104
  • Necela, B.M., Cidlowski, J.A., Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells (2004) Proc. Am. Thorac. Soc., 1, pp. 239-246
  • Kassel, O., Herrlich, P., Crosstalk between the glucocorticoid receptor and other transcription factors: molecular aspects (2007) Mol. Cell. Endocrinol., 275, p. 13
  • Beato, M., Herrlich, P., Schutz, G., Steroid hormone receptors: many actors in search of a plot (1995) Cell, 83, pp. 851-857
  • Besedovsky, H.O., del Rey, A., The cytokine-HPA axis feed-back circuit (2000) Z. Rheumatol., 59 (SUPPL. 2II), pp. 26-30
  • Sapolsky, R.M., McEwen-induced modulation of endocrine history: a partial review (1997) Stress, 2, pp. 1-12
  • Mendoza-Milla, C., Rodriguez, C.M., Córdova Alarcón, E., Estrada Bernal, A., Toledo-Cuevas, M., Martinez Martinez, E., Zentella Dehesa, A., NF-kB activation but not PI3K/Akt is required for dexamethasone dependent protection against TNFα cytotoxicity in L929 cells (2005) FEBS Lett., 579, pp. 3947-3952
  • Alvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrín, D.A., Pecci, A., Burton, G., Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone (2008) J. Med. Chem., 51, pp. 1352-1360
  • Sapolsky, R.M., Romero, L.M., Munck, A.U., How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions (2000) Endocr. Rev., 21, pp. 55-89
  • Newton, R., Holden, N.S., Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? (2007) Mol. Pharmacol., 72, pp. 799-809
  • Mymryk, J.S., Archer, T.K., Influence of hormone antagonists on chromatin remodeling and transcription factor binding to the mouse mammary tumor virus promoter in vivo (1995) Mol. Endocrinol., 9, pp. 1825-1834
  • Fryer, C.J., Archer, T.K., Chromatin remodelling by the glucocorticoid receptor requires the BRG1 complex (1998) Nature, 393, pp. 88-91

Citas:

---------- APA ----------
Pecci, A., Alvarez, L.D., Veleiro, A.S., Ceballos, N.R., Lantos, C.P. & Burton, G. (2009) . New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects. Journal of Steroid Biochemistry and Molecular Biology, 113(3-5), 155-162.
http://dx.doi.org/10.1016/j.jsbmb.2008.12.018
---------- CHICAGO ----------
Pecci, A., Alvarez, L.D., Veleiro, A.S., Ceballos, N.R., Lantos, C.P., Burton, G. "New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects" . Journal of Steroid Biochemistry and Molecular Biology 113, no. 3-5 (2009) : 155-162.
http://dx.doi.org/10.1016/j.jsbmb.2008.12.018
---------- MLA ----------
Pecci, A., Alvarez, L.D., Veleiro, A.S., Ceballos, N.R., Lantos, C.P., Burton, G. "New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects" . Journal of Steroid Biochemistry and Molecular Biology, vol. 113, no. 3-5, 2009, pp. 155-162.
http://dx.doi.org/10.1016/j.jsbmb.2008.12.018
---------- VANCOUVER ----------
Pecci, A., Alvarez, L.D., Veleiro, A.S., Ceballos, N.R., Lantos, C.P., Burton, G. New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects. J. Steroid Biochem. Mol. Biol. 2009;113(3-5):155-162.
http://dx.doi.org/10.1016/j.jsbmb.2008.12.018