Inhibition of human placental aromatase by novel homologated 19-oxiranyl and 19-thiiranyl steroids.
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.
Childers
W E
WE
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Silverton
J V
JV
Kellis
J T
JT
Vickery
L E
LE
Robinson
C H
CH
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047072:Aromatase Inhibitors; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D047072:Aromatase Inhibitors; D004852:Epoxy Compounds; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D000735:Androstenedione