Abstract

The objectives of this proposal are the design, synthesis and evaluation of specific inhibitors of human placental aromatase (estrogen synthetase). These inhibitors include enzyme-generated irreversible inhibitors and also competitive reversible inhibitors. Specific inhibitors of human placental aromatase should be valuable tools in studying estrogen biosynthesis in placental tissue and in other tissues. They may also be of value in the study and treatment of estrogen-dependent tumors, and in studying the role played by peripheral aromatization of androgen in male endocrinology. Mechanistic studies with these inhibitors should also be of interest in further examination of the mechanism of action of aromatase.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD011840-07A1
Application #
3311684
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1978-09-01
Project End
1989-05-31
Budget Start
1985-07-01
Budget End
1986-05-31
Support Year
7
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Oh, S S; Robinson, C H (1993) Mechanism of human placental aromatase: a new active site model. J Steroid Biochem Mol Biol 44:389-97
Childers, W E; Silverton, J V; Kellis Jr, J T et al. (1991) Inhibition of human placental aromatase by novel homologated 19-oxiranyl and 19-thiiranyl steroids. J Med Chem 34:1344-9
Cole, P A; Robinson, C H (1990) Mechanism and inhibition of cytochrome P-450 aromatase. J Med Chem 33:2933-42
Cole, P A; Robinson, C H (1990) Conversion of 19-oxo[2 beta-2H]androgens into oestrogens by human placental aromatase. An unexpected stereochemical outcome. Biochem J 268:553-61
Cole, P A; Bean, J M; Robinson, C H (1990) Conversion of a 3-desoxysteroid to 3-desoxyestrogen by human placental aromatase. Proc Natl Acad Sci U S A 87:2999-3003
Furth, P S; Rosenberger, J; Marcotte, P A et al. (1990) Synthesis of 2,2-dimethyl-4-hydroxy-4-androstene-3,17-dione as an inhibitor of aromatase. J Enzyme Inhib 4:131-5
Furth, P S; Robinson, C H (1989) Tritium release from [19-3H]-19,19-difluoroandrost-4-ene-3,17-dione during inactivation of aromatase. Biochemistry 28:1254-9
Childers, W E; Shih, M J; Furth, P S et al. (1987) Stereoselective inhibition of human placental aromatase. Steroids 50:121-34
Kellis Jr, J T; Childers, W E; Robinson, C H et al. (1987) Inhibition of aromatase cytochrome P-450 by 10-oxirane and 10-thiirane substituted androgens. Implications for the structure of the active site. J Biol Chem 262:4421-6