Structure-activity relationships of a new family of steroidal aromatase inhibitors. 1. Synthesis and evaluation of a series of analogs related to 19-[(methylthio)methyl]androstenedione (RU54115)

Journal of Medicinal Chemistry

Volumn 39, Issue 3, 1996, Pages 757-772

  Lesuisse, Dominique ^a   Gourvest, Jean François ^a   Benslimane, Ouafae ^b   Canu, Frank ^a   Delaisi, Christine ^a   Doucet, Bernard ^a   Hartmann, Catherine ^a   Lefrançois, Jean Michel ^a   Tric, Bernadette ^a   Mansuy, Daniel ^b   Philibert, Daniel ^a   Teutsch, Georges ^a  

^a SANOFI   (France)

^b CNRS   (France)

Author keywords

[No Author keywords available]

Indexed keywords

19 [(METHYLTHIO)METHYL]ANDROSTA 4,9(11) DIENE 3,17 DIONE; ANDROSTENEDIONE; ANTINEOPLASTIC AGENT; AROMATASE; AROMATASE INHIBITOR; ESTRADIOL; RU 54115; SERIC GONADOTROPIN; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BINDING COMPETITION; CANCER INHIBITION; CONTROLLED STUDY; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; HUMAN TISSUE; INHIBITION KINETICS; NONHUMAN; ORAL DRUG ADMINISTRATION; PLACENTA CIRCULATION; RAT; STRUCTURE ACTIVITY RELATION; SUBCUTANEOUS DRUG ADMINISTRATION;

ANIMALS; AROMATASE; AROMATASE INHIBITORS; ENZYME INHIBITORS; ESTRENES; FEMALE; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MICROSOMES; PLACENTA; RATS; SPECTROPHOTOMETRY, INFRARED; STEROIDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0030047384     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm950539l     Document Type: Article

References (41)

1. Lønning, P.E.; Johannessen, D. C. Treatment of Breast Cancer with Aromatase Inhibitors. Drugs Today 1991, 27, 117-32.
2. See, for instance: Banting, L.; Nicholls, P. J.; Shaw, M. A.; Smith, H. J. Recent Developments in Aromatase Inhibition as a Potential Treatment for Oestrogen-Dependent Breast Cancer. In Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.; Elsevier Science Publishers: New York, 1989; Vol. 26, Chapter 2, pp 253-98.
3. Brodie, A. M. H.; Garrit, W. M.; Hendrickson, J. R.; Tsai-Morris, C.-H.; Marcotte, P. A.; Robinson, C. H. Inactivation of Aromatase In Vitro by 4-Hydroxy-4-androstene-3,17-dione and 4-Acetoxy-4-androstene-3,17-dione and Sustained Effects In Vivo. Steroids 1981, 38, 693-702.
4. Metcalf, B. W.; Wright, C. L.; Burkhart, J. P.; Johnston, J. O. Substrate-induced Inactivation of Aromatase by Allenic and Acetylenic Steroids. J. Am. Chem. Soc. 1981, 103, 3221-2.
5. Bhatnagar, A. S.; Haüsler, A.; Schieweck, K.; Lang, M.; Bowman, R. Selective Inhibition of Oestrogen Biosynthesis by CGS 20267, a New Non-steroidal Aromatase Inhibitor. J. Steroid Biochem. Mol.Biol. 1990, 37, 1021-7.
6. De Coster, R.; Wouters, W.; Bowden, C. R.; Vanden Bosche, H.; Bruynseels, J.; Tuman, R. W.; Van Ginckel, R.; Snack, E.; Van Peer, A.; Janssen, P. A. J. New Non-steroidal Aromatase Inhibitor: Focus on R76713. J. Steroid Biochem. Mol.Biol. 1990, 37, 335-92.
7. Delaisi, C.; Doucet, B ; Hartmann, C.; Tric, B.; Gourvest, J. F.; Lesuisse, D. RU54115, A Tight-binding Aromatase Inhibitor Potentially Useful for the Treatment of Breast Cancer. J. Steroid Biochem. Mol.Biol. 1992, 41, 773-7.
8. Lesuisse, D.; Canu, F.; Tric, B. A New Route to 19-Substituted Steroids from 19-Nor Steroids: Sigmatropic [3,3] and [2,3] Rearrangements Revisited. Tetrahedron 1994, 50, 8491-504.
9. Mitsunobu, O. The Use of Diethylazodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products. Synthesis 1981, 1-28.
10. Corey, E. J.; Mehrotra, M. M. A Simple and Enantioselective Synthesis of (+)-Biotin. Tetrahedron Lett. 1988, 29, 57-60.
11. McCarthy, J. R.; Peet, N. P.; LeTourneau, M. E. (Diethylamino)-sulfur Trifluoride in Organic Synthesis. 2. The Transformation of Sulfoxides to α-Fluoro Thioethers. J. Am. Chem. Soc. 1985, 107, 735.
12. Geelen, J. A. A.; Deckers, G. H.; Van der Wardt, J. T. H.; Loozen, H. J. J.; Tax, L. J. W.; Kloosterboer, H. J. Selection of 19-(ethyldithio)-androst-4-ene-3,17-dione (ORG 30958): A Potent Aromatase Inhibitor In Vivo. J. Steroid Biochem. Mol. Biol. 1991, 38, 181-8.
13. Loozen, H. J. J.; Van Luit, P. J. N. EP 0149499, 10.01, 1985.
14. Lesuisse, D.; Gourvest, J. F.; Hartmann, C.; Tric, B.; Benslimane, O.; Philibert, D.; Vevert, J. P. Synthesis and Evaluation of a New Series of Mechanism-Based Aromatase Inhibitors. J. Med. Chem. 1992, 35, 2933-42.
15. 5(6) Steroids Using Dissolved Alkali Metals.) Gazz. Chim. Ital. 1963, 93, 525-41.
16. 5(6) Steroids Using Dissolved Alkali Metals.) Gazz. Chim. Ital. 1963, 93, 525-41.
17. Teutsch, G.; Richard, C. Synthesis of the 10-beta-Ethynyl Analog of Hydrocortisone Acetate. J. Chem. Res. Synop. 1981, 4, 87.
18. Organon, N. V. Fr. Pat. 1,370,970, Aug. 28, 1964; Chem. Abstr. 1965, 62, 1723b.
19. Bucourt, R.; Nédélec, L. Introducing Hydrocarbon Substituents in Position 10 of 19-Norsteroids. Fr. Pat. 1,550,974; Chem. Abstr. 1969, 71, 124799c.
20. Ryan, K. J. Biological aromatization of steroids. J. Biol. Chem. 1972, 234, 268-72.
21. Thompson, E. A.; Siiteri, P. K. Utilization of Oxygen and Reduced Nicotinamide Adenine Dinucleotide Phosphate by Human Placental Microsomes during Aromatization of Androstenedione. J. Biol. Chem. 1974, 249, 5364-72.
22. Kellis, J. T.; Vickery, L. E. Purification and characterization of human placental aromatase cytochrome P-450. J. Biol. Chem. 1987, 262, 4413-20.
23. Williams, G. W.; Morrison, J. F. Kinetics of Reversible Tight-binding Inhibition. Methods Enzymol. 1979, 63, 437-67.
24. Wright, J. N.; Calder, M. R.; Akhtar, M. Steroidal C-19 Sulphur and Nitrogen Derivatives Designed as Aromatase Inhibitors. J. Chem. Soc., Chem. Commun. 1985, 1733.
25. Bednarski, P. J.; Porubek, D. J.; Nelson, S. D. Thiol-Containing Androgens as Suicide Substrates of Aromatase. J. Med. Chem. 1985, 28, 775-9. Bednarski, P. J.; Nelson, S. D. Interactions of Thiol-Containing Androgens with Human Placental Aromatase. J. Med. Chem. 1989, 32, 203-13.
26. Bednarski, P. J.; Porubek, D. J.; Nelson, S. D. Thiol-Containing Androgens as Suicide Substrates of Aromatase. J. Med. Chem. 1985, 28, 775-9. Bednarski, P. J.; Nelson, S. D. Interactions of Thiol-Containing Androgens with Human Placental Aromatase. J. Med. Chem. 1989, 32, 203-13.
27. For general reviews on the mechanism of aromatase, see: (a) Wright, J. N.; Akhtar, M. Studies on Estrogen Biosynthesis using Radioactive and Stable Isotopes. Steroids 1990, 55, 142-51. (b) Cole, P. A.; Robinson, C. H. Mechanism and inhibition of Cytochrome P450 Aromatase. J. Med. Chem. 1990, 33 (11), 2933-42.
28. For general reviews on the mechanism of aromatase, see: (a) Wright, J. N.; Akhtar, M. Studies on Estrogen Biosynthesis using Radioactive and Stable Isotopes. Steroids 1990, 55, 142-51. (b) Cole, P. A.; Robinson, C. H. Mechanism and inhibition of Cytochrome P450 Aromatase. J. Med. Chem. 1990, 33 (11), 2933-42.
29. The chemistry and aromatase-inhibiting properties of this compound will be discussed in part 2 of this series of papers.
30. Kellis, J. T.; Childers, W. E.; Robinson, C. H.; Vickery, L. E. Inhibition of Aromatase Cytochrome P-450 by 10-Oxirane and 10-Thiirane Substituted Androgens. J. Biol. Chem. 1987, 262 (9), 4421-6.
31. Childers, W. E.; Silverton, J. V.; Kellis, J. T.; Vickery, L. E.; Robinson, C. H. Inhibition of Human Placental Aromatase by Novel Homologated 19-Oxiranyl and 19-Thiiranyl Steroids. J. Med. Chem. 1991, 34, 1344-9.
32. de Montellano, P. O. Cytochrome P-450: Structure, Mechanism and Biochemistry; Plenum Press: New-York, London, 1986.
33. Njar, V. C. O.; Safi, E.; Silverton, J. V.; Robinson, C. H. Novel 10β-Aziridinyl Steroids; Inhibitors of Aromatase. J. Chem. Soc., Perkin Trans. I 1993, 1161-8.
34. Kuehn-Velten, N.; Sies, H. Optical Spectral Studies of Ebselen Interaction with Cytochrome P450 of Rat Liver Microsomes. Biochem. Pharmacol. 1989, 38, 619-25.
35. Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution. J. Org. Chem. 1978, 43, 2923-5.
36. Winkle, M. R.; Lansinger, J. M.; Ronald, R. C. 2,5-Dimethoxybenzyl Alcohol: A Convenient Self-indicating Standard for the Determination of Organolithium Reagents. J. Chem. Soc., Chem. Commun. 1980, 87-8.
37. Lowry, O. H.; Rosebrough, N. J.; Farr, A. L.; Randall, R. J. Protein Measurement with the Folin Phenol Reagent. Biol. Chem. 1951, 193, 265.
38. Wright, J. N.; Slatcher, G.; Akhtar, M. "Slow-binding" Sixth-Ligand Inhibitors of Cytochrome P450 Aromatase. Biochem. J. 1991, 273, 533-9.
39. Sethumadhavan, K.; Bellino, F. L. Human Placental Estrogen Synthetase (Aromatase). Effect of Environment on the Kinetics of Protein-Protein Interactions and the Production of 19-Oxygenated Androgen Intermediates in the Purified Reconstituted Cytochrome P450 Enzyme System. J. Steroid Biochem. Mol. Biol. 1991, 39, 381-94.
40. Strobel, H. W.; Dignam, J. D. Purification and Properties of NADPH-Cytochrome P-450 reductase. Methods Enzymol. 1978, 52, 89-97.
41. Lephart, E. D.; Simpson, E. R. Assay of Aromatase Activity. Methods Enzymol. 1991, 206, 477-83.