Effects of Steroid D-Ring Modification on Suicide Inactivation and Competitive Inhibition of Aromatase by Analogues of Androsta-l,4-diene-3,17-dione

Paul F. Sherwin, Patrick C. McMullan, Douglas F. Covey

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Analogues of androsta-l,4-diene-3,17-dione (3a) in which the D ring is modified were prepared and tested as suicide inactivators and competitive inhibitors of human placental aromatase. As long as the five-membered ring is intact, modifications of the D ring such as reduction or removal of the carbonyl group or conversion to aϒ-butyroiactone cause a <6-fold decrease in affinity for and rate of inactivation of aromatase, compared to 3a. Thus, an oxygen atom at C-17 is not required for binding of these inhibitors to aromatase, suggesting that hydrogen bonding to the D-ring oxygen does not play a major role in binding. Opening the D ring converts the cyclopentane ring to an alkyl chain and causes a >300-fold decrease in affinity; this can be partially reversed by shortening the chain length. These results are consistent with a model in which the free chain of the opened D ring adopts conformations that sterically interfere with binding of the inhibitor to the enzyme. These findings may have practical applications in drug design, by allowing the preparation of 17-deoxo analogues that have high affinity for aromatase but that are not subject to reduction of the 17-carbonyl group, which is a major mode of metabolism of 3a.

Original languageEnglish
Pages (from-to)651-658
Number of pages8
JournalJournal of Medicinal Chemistry
Volume32
Issue number3
DOIs
StatePublished - Mar 1 1989

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