NOVEL 10-BETA-AZIRIDINYL STEROIDS - INHIBITORS OF AROMATASE

The novel 10beta-aziridinylestr-4-ene-3,17-diones 17 and 18 and the corresponding 10beta-aziridinyl-17beta-hydroxyestr-4-en-3-ones 19 and 20 have been synthesized from the 19-oximino-19-methyl intermediate 12b. The key reaction was the conversion of the 19-oxime 12b into the diastereoisomeric 10beta-aziridines 13 and 14 by lithium aluminium hydride (LAH). Compounds 17-20 are powerful and stereoselective inhibitors of human placental microsomal aromatase. The most potent compound was 17(Ki = 3.4 nmol dm-3). The 19R-isomers 17 and 19 are more effective than the corresponding 19S-isomers 18 and 20, respectively. Unlike the corresponding 10beta-oxiranes and -thiiranes which are classical competitive inhibitors, the (19R)-aziridines 17 and 19 appear to be slow-binding inhibitors. Spectroscopic studies with microsomal aromatase preparations indicate that the inhibition process involves binding of aziridine nitrogen to the heme-iron of the enzyme.