7-substituted steroidal aromatase inhibitors: structure-activity relationships and molecular modeling

Journal of Enzyme Inhibition
P K Li, R W Brueggemeier

Abstract

Androstenedione analogs containing 7 alpha-substituents 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 Kis ranging from 61 to 174 nM. On the other hand, 7-phenyl-4,6-androstadiene-3,17-dione exhibited poor activity, with an apparent Ki of 1.42 microM. 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 beta position. The 7-benzyl- and 7-phenethyl- groups of 4,6-androstadiene-3,17-diones orient themselves in the minimized structure in a way that the phenyl rings can protrude into the 7 alpha pocket. These orientations are similar to those observed in minimized structures for potent 7 alpha-substituted androstenediones.

References

Jan 1, 1979·Methods in Enzymology·W W Cleland
Oct 1, 1978·Journal of Medicinal Chemistry·R W BrueggemeierR E Counsell
Mar 1, 1975·Journal of Steroid Biochemistry·P K Siiteri, E A Thompson
Mar 1, 1985·Journal of Steroid Biochemistry·C E Snider, R W Brueggemeier
Jun 1, 1985·Journal of Medicinal Chemistry·M V DarbyR E Counsell

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Citations

Sep 11, 2001·American Journal of Therapeutics·R W Brueggemeier
Jan 1, 1994·Breast Cancer Research and Treatment·R W Brueggemeier
Mar 1, 1993·The Journal of Steroid Biochemistry and Molecular Biology·M LangA S Bhatnagar
Aug 30, 2005·Bioorganic & Medicinal Chemistry·Bin SuRobert W Brueggemeier

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