Hydroxyperfluoroazobenzenes: novel inhibitors of enzymes of androgen biosynthesis

Abstract

In a search for inhibitors of 17.alpha.-hydroxylase-C17,20-lyase and testosterone-5.alpha.-reductase, target enzymes in the development of drugs to treat hormone-dependent prostatic cancer, we have identified certain compounds chemically derived by the hydrolysis of decafluoroazobenzene (4) as novel inhibitors for these two enzymes. Hydrolysis of 4 gave the known 4-hydroxyfluoroazobenzene (1) and the novel 2-hydroxynonafluoroazobenzene (2). All AlI3 demethylation of 4,4''-dimethoxyoctafluoroazobenzene (5) or by hydrolysis of 4 under phase-transfer conditions 4,4''-dihydroxyoctafluoroazobenzene (3) was obtained. Compounds 1 and 2 were inhibitors of the hydroxylase (IC50 values, respectively, 30 and 63 .mu.M) and of the lyase (IC50 values 33 and 16 .mu.M) steps on the pathway of androgen biosynthesis. The 2-hydroxy compound 2 underwent spontaneous conversion into octafluorodibenz[b,f][1,4,5]oxadiazepine (6) which had IC50 values, respectively, of 50 and 15 .mu.M for the hydroxylase and lyase steps and which contributed to the observed activity of 2. Effective inhibitors of the 5.alpha.-reductase were 1 (Ki 10 .mu.M) and 3 (Ki 4 .mu.M): the activities of 1 and 3 were markedly pH dependent, with respective IC50 values of 14 and 5 .mu.M at pH 7.4 and of 2 and 0.8 .mu.M at pH 6.6.