7alpha-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 7alpha-thiosubstituted androgens, especially 7alpha-(4'-aminophenylthio)-androsta-1,4-diene-3,17-di one, 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 7alpha position with a carbon-carbon linkage. Several 7alpha-arylaliphatic androst-4-ene-3,17-diones were previously shown to be potent competitive inhibitors of aromatase. The extension of the research on these 7alpha-arylaliphatic androgens includes the introduction of a C1-C2 double bond in the A-ring to provide enzyme-activated irreversible inhibitors. The desired 7alpha-arylaliphatic androsta-1,4-diene-3,17-diones were obtained from their corresponding 7alpha-arylaliphatic androst-4-ene-3,17-diones by oxidation using DDQ. A new improved synthesis of the 7alpha-arylaliphatic androst-4-ene-3,17-diones using an in situ preparation of the CuI-(n-Bu3)P complex was employed. The aryl ring of the 7alpha-phenethyl and 7alpha-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 enzyme-mediated inactivation of aromatase with apparent k(inact)s ranging from 4.4 x 10(-4) to 1.90 x 10(-3)/s. The best inactivator of the series was the 7alpha-phenpropylandrosta-1,4-diene-3,17-dione, which exhibited a T(1/2) of 6.08 min.