Evaluation of 6,7-Aziridinyl Steroids and Related Compounds as Inhibitors of Aromatase (P-450_arom)

Abstract

Inhibitors of human placental aromatase (P-450_arom) may be useful in treating estrogen-dependent diseases (e.g. breast cancer). Some 6,7-aziridinyl steroids and related compounds (fused steroidal oxiranes, azidohydrins and an azide) were evaluated as inhibitors of this enzyme. Although the 6,7-aziridines and their N- derivatives are poor inhibitors of the enzyme (IC₅₀ values 49- >>250 μM), most of the other compounds are modest inhibitors (IC₅₀ values 3.0-15.0 μM), while 6β-azido-7α-acetoxyandrost-4-ene-3,17-dione (10) is a potent inhibitor of the enzyme (IC₅₀ value = 0.4 μM, K_i = 14 nM). The difference in inhibitory potency between 10 and the parent compound, 6β-azido-7α-hydroxyandrost-4-ene-3,17-dione (9), (IC₅₀ value = 47 μM, K_i = 294 nM) is striking and unexpected. The inhibitory potency of 10 is comparable to that of formestane (4-hydroxyandrost-4-ene-3,17-dione, 4-OHA, 16) (IC₅₀ value = 0.6 μM, K, = 9 nM), an inhibitor of aromatase which recently has been approved for clinical use in breast cancer treatment. Our most active inhibitors, 10 and 7α-azido-6β-hydroxyandrost-4-ene-3,17-dione (11) (at concentrations of 125 μM each) did not inhibit the rat 17α-hydroxylase/C_17,20-lyase (17α-lyase) enzyme.

Key Words: :

• Human placental aromatase (P-450_arom)
• 6,7-substituted analogues of androstenedione
• aromatase inhibitors