Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone

Journal of Medicinal Chemistry

Volumn 51, Issue 5, 2008, Pages 1352-1360

  Álvarez, Lautaro D ^a   Martí, Marcelo A ^a   Veleiro, Adriana S ^a   Presman, Diego M ^b   Estrin, Darío A ^a   Pecci, Adalí ^b   Burton, Gerardo ^a  

^a UNIVERSIDAD DE BUENOS AIRES   (Argentina)

^b INSTITUTO DE FISIOLOGÍA   (Argentina)

Author keywords

[No Author keywords available]

Indexed keywords

21 HYDROXY 6,19 EPOXYPROGESTERONE; DEXAMETHASONE; GLUCOCORTICOID ANTAGONIST; GLUCOCORTICOID RECEPTOR; HOMODIMER; TRANSCRIPTOME; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; DRUG MECHANISM; GENE ACTIVATION; GENE LOCATION; GENE TRANSLOCATION; MOLECULAR DYNAMICS; MOUSE; NONHUMAN; TRANSACTIVATION;

ANIMALS; BINDING SITES; CELL LINE; CELL NUCLEUS; CRYSTALLOGRAPHY, X-RAY; DEXAMETHASONE; DIMERIZATION; GENES, REPORTER; LIGANDS; MICE; MICROSCOPY, CONFOCAL; MODELS, MOLECULAR; PROGESTERONE; PROMOTER REGIONS (GENETICS); PROTEIN TRANSPORT; RECEPTORS, GLUCOCORTICOID; TRANS-ACTIVATION (GENETICS);

EID: 41649098153     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800007w     Document Type: Article

References (38)

1. Necela, B. M.; Cidlowski, J. A. Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc. Am. Thorac. Soc. 2004, 1, 239-246.
2. Moore, J. T.; Collins, J. L.; Pearce, K. H. The nuclear receptor superfamily and drug discovery. ChemMedChem 2006, 1, 504-523.
3. Farman, N.; Bocchi, B. Mineralocorticoid selectivity: molecular and cellular aspects. Kidney Int. 2000, 57, 1364-1369.
4. Wambach, G.; Higgins, J. R. Antimineralocorticoid action of progesterone in the rat: correlation of the effect on electrolyte excretion and interaction with renal mineralocorticoid receptor. Endocrinology 1978, 102, 1686-1693.
5. Kumar, R.; Thompson, E. B. Gene regulation by the glucocorticoid receptor: structure:function relationship. J. Steroid Biochem. Mol. Biol. 2005, 94, 383-394.
6. Herr, I.; Pfitzenmaier, J. Glucocorticoid use in prostate cancer and other solid tumours: implications for effectiveness of cytotoxic treatment and metastases. Lancet Oncol. 2006, 7, 425-430.
7. Zhang, C.; Beckermann, B.; Kallifatidis, G.; Liu, Z.; Rittgen, W.; Edler, L.; Buchler, P.; Debatin, K. M.; Buchler, M. W.; Friess, H.; Herr, I. Corticosteroids induce chemotherapy resistance in the majority of tumour cells from bone, brain, breast, cervix, melanoma and neuroblastoma. Int. J. Oncol. 2006, 29, 1295-1301.
8. Necela, B. M.; Cidlowski, J. A. Crystallization of the human glucocorticoid receptor ligand binding domain: a step towards selective glucocorticoids. Trends Pharmacol. Sci. 2003, 24, 58-61.
9. (a) Teutsch, J. G.; Costerousse, G.; Philibert, D.; Deraedt, R. Novel Steroids. U.S. Patent 4,386,085, 1983.
10. (b) Spitz, I. M.; Bardin, C. W. Mifepristone (RU-486): a modulator of progestin and glucocorticoid action. N. Engl. J. Med. 1993, 329, 404-412.
11. Zhang, J.; Tsai, F. T.; Geller, D. S. Differential interaction of RU486 with the progesterone and glucocorticoid receptors. J. Mol. Endocrinol. 2006, 37, 163-173.
12. Gronemeyer, H.; Gustafsson, J. A.; Laudet, V. Principles for modulation of the nuclear receptor superfamily. Nat. Rev. Drug Discov. 2004, 3, 950-964.
13. Bledsoe, R. K.; Montana, V. G.; Stanley, T. B.; Delves, C. J.; Apolito, C. J.; McKee, D. D.; Consler, T. G.; Parks, D. J.; Stewart, E. L.; Willson, T. M.; Lambert, M. H.; Moore, J. T.; Pearce, K. H.; Xu, H. E. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 2002, 110, 93-105.
14. Chen, J. D.; Evans, R. M. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 1995, 377, 454-457.
15. Brzozowski, A. M.; Pike, A. C.; Dauter, Z.; Hubbard, R. E.; Bonn, T.; Engstrom, O.; Ohman, L.; Greene, G. L.; Gustafsson, J. A.; Carlquist, M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997, 389, 753-758.
16. Shiau, A. K.; Barstad, D.; Loria, P. M.; Cheng, L.; Kushner, P. J.; Agard, D. A.; Greene, G. L. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998, 95, 927-937.
17. Shiau, A. K.; Barstad, D.; Radek, J. T.; Meyers, M. J.; Nettles, K. W.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Agard, D. A.; Greene, G. L. Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat. Struct. Biol. 2002, 9, 359-364.
18. Singh, S. M.; Gauthier, S.; Labrie, F. Androgen receptor antagonists (antiandrogens): structure-activity relationships. Curr. Med. Chem. 2000, 7, 211-247.
19. Souque, A.; Fagart, J.; Couette, B.; Davioud, E.; Sobrio, F.; Marquet, A.; Rafestin-Oblin, M. E. The mineralocorticoid activity of progesterone derivatives depends on the nature of the C18 substituent. Endocrinology 1995, 136, 5651-5658.
20. Honer, C.; Nam, K.; Fink, C.; Marshall, P.; Ksander, G.; Chatelain, R. E.; Cornell, W.; Steele, R.; Scweitzer, R.; Schumacher, C. Glucocorticoid receptor antagonism by cyproterone acetate and RU486. Mol. Pharmacol. 2003, 63, 1012-1020.
21. Weeks, C. M.; Duax, W. L.; Wolf, M. E. Comparison of the molecular structures of six corticosteroids. J. Am. Chem. Soc. 1976, 95, 2865-2868.
22. Vicent, G. P.; Monteserin, 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. Mol. Pharmacol. 1997, 52, 749-753.
23. Cadepond, F.; Ulmann, A.; Baulieu, E. E. RU486 (mifepristone): mechanisms of action and clinical uses. Annu. Rev. Med 1997, 48, 129-156.
24. Kauppi, B.; Jakob, C.; Farnegardh, M.; Yang, J.; Ahola, H.; Alarcon, M.; Calles, K.; Engstrom, O.; Harlan, J.; Muchmore, S.; Ramqvist, A. K.; Thorell, S.; Ohman, L.; Greer, J.; Gustafsson, J. A.; Carlstedt-Duke, J.; Carlquist, M. The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J. Biol. Chem. 2003, 278, 22748-54.
25. Patel, F. A.; Funder, J. W.; Challis, J. R. 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. J. Clin. Endocrinol. Metab. 2003, 88, 2922-33.
26. Hillisch, A.; von Langen, J.; Menzenbach, B.; Droescher, P.; Kaufmann, G.; Schneider, B.; Elger, W. The significance of the 20-carbonyl group of progesterone in steroid receptor binding: a molecular dynamics and structure-based ligand design study. Steroids 2003, 68, 869-878.
27. von Langen, J.; Fritzemeier, K. H.; Diekmann, S.; Hillisch, A. Molecular basis of the interaction specificity between the human glucocorticoid receptor and its endogenous steroid ligand cortisol. ChemBioChem 2005, 6, 1110-1118.
28. Williams, S. P.; Sigler, P. B. Atomic structure of progesterone complexed with its receptor. Nature 1998, 393, 392-396.
29. Bourguet, W.; Ruff, M.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature 1995, 375, 377-382.
30. Horwitz, K. B.; Zava, D. T.; Thilagar, A. K.; Jensen, E. M.; McGuire, W. L. Steroid receptor analyses of nine human breast cancer cell lines. Cancer Res. 1978, 38, 2434-2437.
31. Beato, M. H.; Schütz, P. G. Steroid hormone receptors: Many Actors in search of a plot. Cell 1995, 83, 851-857.
32. Burton, G.; Lantos, C. P.; Veleiro, A. S. Method for the preparation of 21-hydroxy-6,19-oxidoprogesterone (21OH-6OP). U.S. Patent 7,071,328, 2006.
33. Veleiro, A. S.; Pecci, A.; Monteserin, M. C.; Baggio, R.; Garland, M. T.; Lantos, C. P.; Burton, G. 6,19-Sulfur-bridged progesterone analogues with antiimmunosuppressive activity. J. Med. Chem. 2005, 48, 5675-5683.
34. Gaussian 03, Revision B.05:Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc., Pittsburgh, PA, 2003.
35. Pearlman, D. A.; Case, D. A.; Caldwell, J. W.; Ross, W. S.; Cheatham Iii, T. E.; DeBolt, S.; Ferguson, D.; Seibel, G.; Kollman, P. AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Comput. Phys. Commun. 1995, 91, 1-41.
36. Berendsen, H. J. C.; Postma, J. P. M.; Van Gunsteren, W. F.; DiNola, A.; Haak, J. R. Molecular dynamics with coupling to an external bath. J. Chem. Phys. 1984, 81, 3684-3690.
37. CheathaIii, T. E.; Cieplak, P.; Kollman, P. A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat Biomol. Struct. Dynam. 1999, 16, 845-862.
38. Amadei, A.; Linssen, A. B. M.; Berendsen, H. J. C. Essential dynamics of proteins. Proteins: Structure, Funct. Genet. 1993, 17, 412-425.