Inhibition of aromatase by steroids substituted at C-19 with halogen, sulphur, and nitrogen
Abstract
The known displacement of 19-methanesulphonates in 3-acetoxy-5-ene steroids was extended to the bis(ethylene acetal) compounds (12) to provide a convenient route to 19-halogenoandost-4-ene-3,17-diones (10 m,n,o). It was discovered that iodine in the 19 position in compounds (7) and (13) can be smoothly displaced by reactive nucleophiles (CN–, MeSO2S–, N3–) without rearrangement. This enabled us to synthesize a series of steroid derivatives, containing sulphur and nitrogen at C-19, which were tested as aromatase inhibitors. Of potential interest were the 19-thioalkyl compounds (10 f–j) which showed increasing competitive inhibition as the size of the alky substituent decreased. The most potent was the 1 9-thiomethylandrost-4-ene-3,17-dione (10f)(Ki= 1 × 10–9M). The most potent of the 19-aza steroids was 19-azidoandrost-4-ene-3,17-dione (10d)(Ki= 5 × 10–9M). It is proposed that both these inhibitors act by providing a sixth ligand to the haem iron of cytochrome P-450 (arom).