Synthesis and Evaluation of 4-(Substituted thio)-4-androstene-3,17-dione Derivatives as Potential Aromatase Inhibitors

Yusuf J. Abul-Hajj

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42 Scopus citations

Abstract

The synthesis and evaluation of 4-(substituted thio)-4-androstene-3,17-dione derivatives as inhibitors of estrogen synthetase (aromatase) are described. All compounds were prepared by the addition of various thiol reagents to 4β,5β-epoxyandrostanedione. Inhibitory activity of synthesized compounds was determined with use of 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 36 to 73 nM, with the apparent Km for androstenedione being 53 nM. The results of these studies demonstrate a tightly fitted enzyme pocket that can accommodate bulk up to about 5.5 Å.

Original languageEnglish (US)
Pages (from-to)582-584
Number of pages3
JournalJournal of medicinal chemistry
Volume29
Issue number4
DOIs
StatePublished - Jan 1 1986

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