7α-Arylaliphatic androsta-1,4-diene-3,17-diones as enzyme-activated irreversible inhibitors of aromatase

Abstract Inhibition of aromatase, the enzyme responsible for converting androgens to estrogens, may be therapeutically useful for the endocrine treatment of hormone-dependent breast cancer. Previous research on 7α-thiosubstituted androgens, especially 7α-(4′-aminophenylthio)-androsta-1,4-diene-3,17-dione, has shown that these compounds are potent enzyme-activated irreversible inhibitors of aromatase. Research on the synthesis of more metabolically stable inhibitors has focused on replacing the thioether linkage at the 7α position with a carbon-carbon linkage. Several 7α-arylaliphatic androst-4-ene-3,17-diones were previously shown to be potent competitive inhibitors of aromatase. The extension of the research on these 7α-arylaliphatic androgens includes the introduction of a C 1 C 2 double bond in the A-ring to provide enzyme-activated irreversible inhibitors. The desired 7α-arylaliphatic androsta-1,4-diene-3,17-diones were obtained from their corresponding 7α-arylaliphatic androst-4-ene-3,17-diones by oxidation using DDQ. A new improved synthesis of the 7α-arylaliphatic androst-4-ene-3,17-diones using an in situ preparation of the CuI-(n-Bu 3 )P complex was employed. The aryl ring of the 7α-phenethyl and 7α-phenpropyl derivatives were functionalized to their corresponding p -nitro and p -amino derivatives. These compounds were all potent inhibitors of aromatase with apparent K i s ranging between 7 and 19 nM. These inhibitors demonstrated enzymemediated inactivation of aromatase with apparent k inact s ranging from 4.4 × 10 −4 to 1.90 × 10 −3 /s. The best inactivator of the series was the 7α-phenpropylandrosta-1,4-diene-3,17-dione, which exhibited a T 1 2 of 6.08 min.