Abstract
Novel homologated 19-oxiranyl- and 9-thiiranylandrost-4-ene-3,17-diones (8a,b and 9a,b, respectively) have been synthesized. The configuration and conformation of compound 8a have been established by X-ray crystallographic analysis. All four compounds have been shown to be competitive inhibitors of human placental aromatase. The thiiranes were more potent inhibitors than the corresponding oxiranes, and the 2'S isomers (8b and 9b) were better inhibitors than the 2'R (8a and 9a) diastereomers in each series. Spectroscopic studies with purified human placental aromatase suggest that the oxiranyl oxygen and thiiranyl sulfur of 2'S compounds 8b and 9b coordinate to the enzyme's heme iron.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Androstenedione / analogs & derivatives*
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Androstenedione / chemical synthesis*
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Androstenedione / chemistry
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Androstenedione / pharmacology
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Aromatase Inhibitors*
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Epoxy Compounds / chemical synthesis*
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Epoxy Compounds / chemistry
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Epoxy Compounds / pharmacology
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Female
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology
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Humans
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Indicators and Reagents
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Kinetics
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Placenta / enzymology*
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Pregnancy
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Spectrophotometry, Infrared
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Structure-Activity Relationship
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X-Ray Diffraction
Substances
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Aromatase Inhibitors
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Epoxy Compounds
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Heterocyclic Compounds
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Indicators and Reagents
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Androstenedione