Evaluation of 6,7-aziridinyl steroids and related compounds as inhibitors of aromatase (P-450arom)

J Enzyme Inhib. 1995;9(3):195-202. doi: 10.3109/14756369509021485.

Abstract

Inhibitors of human placental aromatase (P-450arom) 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 3.0-15.0 microM), while 6 beta-azido-7 alpha-acetoxyandrost-4-ene-3,17-dione (10) is a potent inhibitor of the enzyme (IC50 value = 0.4 microM, Ki = 14 nM). The difference in inhibitory potency between 10 and the parent compound, 6 beta-azido-7 alpha-hydroxyandrost-4-ene-3,17-dione (9), (IC50 value = 47 microM, Ki = 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 microM, Ki = 9 nM), an inhibitor of aromatase which recently has been approved for clinical use in breast cancer treatment. Our most active inhibitors, 10 and 7 alpha-azido-6 beta-hydroxyandrost-4-ene-3,17-dione (11) (at concentrations of 125 microM each) did not inhibit the rat 17 alpha-hydroxylase/C17,20-lyase (17 alpha-lyase) enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstenedione / analogs & derivatives*
  • Androstenedione / pharmacology
  • Aromatase Inhibitors*
  • Aziridines / chemistry
  • Aziridines / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Kinetics
  • Microsomes / enzymology
  • Molecular Structure
  • Placenta / enzymology
  • Steroid Hydroxylases / antagonists & inhibitors
  • Steroid Hydroxylases / metabolism

Substances

  • Aromatase Inhibitors
  • Aziridines
  • Enzyme Inhibitors
  • Androstenedione
  • Steroid Hydroxylases