6β-Propynyl-substituted steroids: Mechanism-based enzyme-activated irreversible inhibitors of aromatase

Journal of Medicinal Chemistry

Volumn 40, Issue 20, 1997, Pages 3263-3270

  Akkani, Abraham ^a   Paterlini, Germana ^a   Gleason, William B ^a,b   Ojala, William H ^b   Abul Hajj, Yusuf J ^a,c  

^a UNIVERSITY OF MINNESOTA   (United States)

^b UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF MINNESOTA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6BETA PROPARGYL 4 ANDROSTENE 3,17 DIONE; 6BETA PROPARGYLESTR 4 ENE 3,17 DIONE; ANDROSTENEDIONE DERIVATIVE; AROMATASE; AROMATASE INHIBITOR; ESTRANE DERIVATIVE; ESTROGEN; MERCAPTOETHANOL; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; UNCLASSIFIED DRUG;

AROMATIZATION; ARTICLE; BREAST CANCER; CONTROLLED STUDY; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; INHIBITION KINETICS; MICROSOME; MOLECULAR MODEL; PLACENTA; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

AROMATASE INHIBITORS; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HUMANS; KINETICS; MODELS, MOLECULAR; PROTEIN CONFORMATION; STEROIDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0030866071     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970325z     Document Type: Article

References (36)

1. Oh, S. S.; Robinson, C. H. Mechanism of Human Placental Aromatase: A New Active Site Model. J. Steroid Biochem. Mol. Biol. 1993, 44, 389-397.
2. Akhtar, M.; Njar, V. C. O.; Wright, J. N. Mechanistic Studies on Aromatase and Related C-C Bond Cleavage P-450 Enzymes. J. Steroid Biochem. Mol. Biol. 1993, 44, 375-387.
3. Covey, D. F.; Hood, W. F.; Parikh. V. D. 10β-Propynyl-substituted Steroids. J. Biol. Chem. 1981, 256, 1076-1079.
4. Metcalf, B. W.; Wright, C. L.; Burkhart, J. P.; Johnston, J. O. Substrate-induced Inactivation of Aromatase by Allenic and Acetylinic Steroids. J. Am. Chem. Soc. 1981, 103, 3221-3222.
5. Abul-Hajj, Y. J., Liu, X.-P.; Hedge, M. Synthesis and Evaluation of Substituted-4-androstene-3,17-dione Derivatives as Aromatase Inhibitors. J. Steroid Biochem. Mol. Biol. 1995, 54, 111-119.
6. O'Reilly, J. M.; Williams, N. L.; Duax, W. L.; Brueggemeier, R. W. Synthesis, Structure Elucidation, and Biochemical Evaluation of 7α and 7β- Arylaliphatic-substituted Androst-4-ene-3,-17-diones as Inhibitors of Aromatase. J. Med. Chem. 1995, 38, 2842-2850.
7. Brodie, A. M.; Schwarzel, W. C.; Sheikh, A. A.; Brodie, H. J. The Effect of an Aromatase Inhibitor, 4-Hydroxy-4-androstene-3,-17-dione, on Estrogen Dependent Progress in Reproduction and Breast Cancer. Endocrinology 1977, 100, 1684-1695.
8. Bednarski, P. J.; Nelson, S. D. Interactions of Thiol-containing Androgens with Human Placental Aromatase. J. Med. Chem. 1989, 32, 203-213.
9. 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, 4421-4426.
10. Osawa, Y.; Osawa, Y.; Coon, M. J. Stereochemistry of the Functional Group Determines the Mechanism of Aromatase Inhibition by 6-Bromoandrostenedione. Endocrinology 1987, 121, 1010-1016.
11. Laughton, C. A.; Neidle, S. Inhibition of the P450 Enzymes Aromatase and Lyase. Crystallograhic and Molecular Modeling Studies Suggest Structural Features of Pyridylacetic Acid Derivatives Responsible for Differences in Enzymic Inhibitory Activity. J. Med. Chem. 1990, 33, 3050-3060.
12. Brueggemeier, R. W.; Floyd, E. E.; Counsell, R. E. Synthesis and Biochemical Evaluation of Inhibitors of Estrogen Biosynthesis. J. Med. Chem. 1978, 27, 1007-1011.
13. Abul-Hajj, Y. J. Synthesis and Evaluation of 4-(Substituted thio)-4-androstenedione Derivatives as Potential Aromatase Inhibitors. J. Med. Chem. 1986, 29, 582-584.
14. Liu, X.-P.; Lambert, D. M.; Abul-Hajj, Y. J. Probing the Hydrophobic Pocket of the Active Site of Aromatase with 4-Phenoxy-7α-thiophenyl-4-androstenedione. J. Med. Chem. 1995, 38, 4135-4138.
15. Kellis, J. T.; Vickery, L. E. The Active Site of Aromatase Cytochrome P-450. J. Biol. Chem. 1987, 262, 8840-8844.
16. Chen, S.; Zhou, D.; Swiderek, K. M.; Kadohama, N.; Osawa, Y.; Hall, P. F. Structure-Function Studies of Human Aromatase. J. Steroid Biochem. Mol. Biol. 1993, 44, 347-356.
17. Graham-Lorence, S.; Khalil, M. W.; Lorence, M. C.; Mendelson, C. R.; Simpson, E. R. Structure-Function Relationship of Human Aromatase Cytochrome P-450 Using Molecular Modeling and Site-Directed Mutagenesis. J. Biol. Chem. 1991, 266, 11939-11946.
18. Laughton, C. A.; Zvelebil, M. J. J. M.; Neidle, S. A Detailed Molecular Model for Human Aromatase. J. Steroid Biochem. Mol. Biol 1993, 44, 399-407.
19. Graham-Lorence, S.; Amarneh, B.; White, R. E.; Peterson, J. A.; Simpson, E. R. A Three-Dimennsional Model of Aromatase Cytochrome P450. Protein Sci. 1995, 4, 1065-1080.
20. Santen, R. J.; Manni, A.; Harvey, H.; Redmond, C. Endocrine Treatment of Breast Cancer. Endocrine Rev. 1990, 2, 1-45.
21. Campbell, J. A.; Babcock, J. C.; Hogg, J. A. 6-Methylsteroids in the androstane series. J. Am. Chem. Soc. 1958, 80, 4714-4721.
22. Viollotti, R.; Djerassi, C.; Ringold, H. J. Steroids. CXXIII. 19-Nor-6-methylandrostane Derivatives. J. Am. Chem. Soc. 1959, 81, 4566-4570.
23. Terasawa, T. Aromatase Inhibition by Steroid Derivatives. Jap. Patent 63-45294, February 26, 1988.
24. Numazawa, M.; Oshibe, M. 6-Alkyl- and 6-Arylandrost-4-ene-3,17-dione as Aromatase Inhibitors. Synthesis and Structure-Activity Relationships. J. Med. Chem. 1994, 33, 1312-1319.
25. Thompson, A. E., Jr.; Siiteri, P. K. The Involvement of Human Placental Microsomal P-450 in Aromatization. J. Biol. Chem. 1974, 249, 5373-5378.
26. Numazawa, M.; Oshibe, M. Further Studies on 6-Alkylandrost-4-ene-3,17-dione as Aromatase Inhibitors: Elongation of the 6-Alkyl Chain. Steroids 1995, 60, 576-581.
27. Kitz, R.; Wilson, I. B. Esters of methansulfonic acid as irreversible inhibitors of acetycholinesterase. J. Biol. Chem. 1962, 237, 3245-3249.
28. cam. J. Mol. Biol, 1987, 195, 687-700.
29. Ryan, K. J. Biological Aromatization of Steroids. J. Biol. Chem. 1959, 234, 266-272.
30. Reed, K. C.; Ohno, S. Kinetic properties of human placental aromatase. J. Biol. Chem. 1976, 251, 5373-5378.
31. Cleland, W. W. The statistical analysis of enzyme kinetic data. Methods Enzymol. 1979, 63, 103-138.
32. Biosym Technologies, 9685 Scranton Rd., San Diego, CA 92121-2777.
33. Gaussian Inc., Carnegie Office Park, Pittsburgh, PA 15106.
34. North, A. C. T.; Phillips, D. C.; Mathews, F. S. A semiempirical method of absorption correction. Acta Crystallogr. Sect. A 1968, 24, 351-359.
35. SHELXS 86. Program for the solution of crystal structures University of Göttingen, Germany, 1985.
36. TEXSAN-TEXRAY. Structure Analysis Package, Molecular Structure Corporation, The Woodlands, TX, 1985.