Aromatase inhibition by 4-thiosubstituted-4-androstene-3,17-dione derivatives

Yusuf J. Abul-Hajj

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

The synthesis and evaluation of 4-thiosubstituted-4-androstenedione analogs as inhibitors of estrogen synthetase (aromatase) is described. All compounds were prepared by the addition of various thiol reagents to 4β,5β-epoxyandrostanedione. Inhibitory activity of synthesized compounds was assessed using a human placental microsomal preparation as the enzyme source and [1β-3H]4-androstene-3,17-dione as substrate. Synthesized compounds exhibiting high inhibitory activity were further evaluated under initial velocity conditions to determine apparent Ki values. Several compounds were effective competitive inhibitors, and have apparent Ki values ranging from 34 to 52 nM, with the apparent Km for androstenedione being 54 nM. The results of these studies demonstrate a tightly fitted enzyme pocket that can accommodate bulky substituents at the C-4 position of androstenedione not to exceed 4.3 Å in width and 5.5 Å in length.

Original languageEnglish (US)
Pages (from-to)139-143
Number of pages5
JournalJournal of Steroid Biochemistry
Volume35
Issue number1
DOIs
StatePublished - Jan 1990

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