Model Studies for the Mechanism of Inactivation of Monoamine Oxidase by 5-(Aminomethyl)-3-ary1-2-oxazolidinones

Kent S. Gates, Richard B Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

3-[4-[(3-Chlorophenyl)methoxylphenyl]-5-[(methylamino)methyl]-2-oxazolidinone (MD 780236) has been reported to be an irreversible inactivator of monoamine oxidase (MAO), but the mechanism of inactivation is not known. A mechanism is now proposed that involves one-electron transfer to give the corresponding amine radical cation, removal of an a-proton, and decomposition of the oxazolidinone ring with loss of CO2to another radical which attaches to an enzyme active site radical. Chemical model studies for the proposed inactivation mechanisms are reported. Treatment of 3-(4-methoxyphenyl)-5-(chloromethyl)-2-oxazolidinone with tributylstannane and AIBN at 190 °C gave N-allylanisidine (6%) and CO2in addition to the hydrogen atom rebound product 3-(4-methoxypheny1)-5-methyl-2-oxazolidinone. A high yield of N-allylanisidine was obtained by treatment of the corresponding bromo analogue with zinc, magnesium, or n-butyllithium. These studies support a radical inactivation mechanism that may proceed through additional carbon radical or carbanion intermediates. MD 780236 labeled with 14C at the carbonyl of the oxazolidinone ring inactivates MAO with loss of 14CO2, consistent with the model study results.

Original languageEnglish (US)
Pages (from-to)8891-8895
Number of pages5
JournalJournal of the American Chemical Society
Volume111
Issue number24
DOIs
StatePublished - Nov 1 1989

ASJC Scopus subject areas

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

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