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)(K_i= 1 × 10^–9M). The most potent of the 19-aza steroids was 19-azidoandrost-4-ene-3,17-dione (10d)(K_i= 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).