Chemical Model for a Mechanism of Inactivation of Monoamine Oxidase by Heterocyclic Compounds. Electronic Effects on Acetal Hydrolysis

Richard B. Silverman, Charles Z. Ding

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Monoamine oxidase (MAO) was shown previously to undergo time-dependent inhibition by 5-(aminomethyl)-3-(4-methoxyphenyl)-2-oxazolidinone (3, X = N, Y = O, R = Me, R′ = H), cis- and trans-5-(aminomethyl)-3-(4-methoxyphenyl) dihydrofuran-2(3H)-one (5, R = Me), and 4-(aminomethyl)-l-(4-methoxyphenyl)-2-pyrrolidinone (6, R = Me). Two approaches are taken in this article to test the hypothesis that the cause for this inhibition is electron-withdrawing stabilization of an enzyme adduct by the heterocycles. First, the rates of reactivation of the inhibited enzyme were measured, and they correlated qualitatively with the strengths of the electron-withdrawing abilities of the heterocycles. The second approach was a chemical model study for the proposed enzyme adduct stabilities. The corresponding acetals were synthesized, and the rates of acid hydrolysis of these acetals were used as a model for the decomposition of the enzyme adducts; the rates of hydrolysis should be a qualitative measure of the stabilities of the enzyme adducts. An inverse relationship was observed between the strength of the electron-withdrawing effect of the heterocycle and the rate of acetal hydrolysis. These results support the hypothesis that inhibition of MAO by heterocyclic compounds results from electronic stabilization of the enzyme adducts produced. This realization should prove to be very beneficial to the design of new classes of MAO inhibitors. Furthermore, it cautions synthetic chemists as to the problems associated with acetal deprotection of aldehydes when electron-withdrawing groups are even three bonds away from the acetal carbon.

Original languageEnglish (US)
Pages (from-to)4571-4576
Number of pages6
JournalJournal of the American Chemical Society
Volume115
Issue number11
DOIs
StatePublished - Jun 1 1993

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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