7-Substituted Steroidal Aromatase Inhibitors: Structure-Activity Relationships and Molecular Modeling

Abstract

Androstenedione analogs containing 7α-substitutents have proven to be potent inhibitors of aromatase both in vitro and in vivo. Several of these agents have exhibited higher affinity for the enzyme complex than the substrate does. In order to examine further the interaction(s) of 7-substituted steroids with aromatase, biochemical and molecular modeling studies were performed on 7-substituted 4,6-androstadiene-3,17-diones. 7-Benzyl- and 7-phenethyl-4,6-androstadiene-3,17-diones effectively inhibited microsomal aromatase, with apparent K_is ranging from 61 to 174nM. On the other hand, 7-phenyl-4,6-androstadiene-3,17-dione exhibited poor activity, with an apparent K_i of 1.42μM. Energy minimization calculations and molecular modeling indicated that the 7-substituent is perpendicular to the steroid nucleus in the 7-phenyl analog and can only adopt a pseudo β position. The 7-benzyl- and 7-phenethyl- groups of 4,6-andros-tadiene-3,17-diones orient themselves in the minimized structure in a way that the phenyl rings can protrude into the 7α pocket. These orientations are similar to those observed in minimized structures for potent 7α-substituted androstenediones.

Key Words: :

• Aromatase inhibition
• 7α-APTA
• 7α-APTADD
• 7-substituted 4,6-androstadiene-3,17-diones
• structure-activity relationships
• molecular modeling
• conformational analysis