Novel 19-(Cyclopropylamino)-Androst-4-EN-3,17-Dione: a Mechanism-Based Inhibitor of Aromatase

Abstract

The novel 19-(cyclopropylamino)-androst-4-en-3,17-dione (5, CPA), a mechanism-based inhibitor of aromatase has been synthesized from the l0β op-aldehyde intermediate (2). The key reaction was the trifluoroacetic acid-catalysed condensation of 2 with cyclopropylamine in refluxing toluene to give the 19-cyclopropylimine (3). Enzyme inhibition studies show that CPA is a time-dependent, irreversible inhibitor of human placental microsomal aromatase (K_i = 92±2 nM). The inactivation of aromatase by CPA was NADPH-dependent and was protected by the presence of substrate testosterone (20 μM). In addition, the inactivation was not affected by the nucleophile, L-cysteine (0.5 mM), suggesting retention of the inhibitor in the enzyme's active site during the inactivation process.

Key Words: :

• Human placental aromatase
• 19-(cyclopropylamino)-androst-4-en-3,17-dione
• mechanism-based aromatase inactivator