5-(Aminomethyl)-3-aryl-2-oxazolidinones. A Novel Class of Mechanism-Based Inactivators of Monoamine Oxidase B

Kent S. Gates, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

The mechanism of inactivation of monoamine oxidase (MAO) by 5-(aminomethyl)-3-aryl-2-oxazolidinones has been investigated. (R)- and (S)-3-[4-[(3-chlorophenyl)methoxy]phenyl]-5-[(methylamino)methyl]-2-oxazolidinone (1) exhibit all of the properties of a mechanism-based inactivator. Several other analogues of 1 also inactivate MAO. Inactivation of MAO by (R)- and (5)-[methoxy-3H]-1 and by [methoxy-3H]-3-(4-methoxyphenyI)-5-[(methylamino)methyl]-2-oxazolidinone (15, R = 3H) led to incorporation of 1.0, 1.2, and 2.1 equiv of tritium per enzyme molecule after denaturation, indicating that a covalent bond between the oxazolidinones and MAO is formed. The partition ratios, determined from the amount of radioactive non-amines generated per tritium incorporated into the enzyme, were 17.6 and 10.9 for the R and 5 isomers, respectively. Inactivation of MAO by (R)- and (S)-[carboxy-14C]-1 resulted in release of 4.5 and 3.0 equiv of 14CO2, respectively. However, in addition to the loss of 14CO2 there also was incorporation of 1.5 and 1.0 equiv of 14C, respectively, into the enzyme after denaturation. The flavin spectrum indicated that the flavin was reduced after inactivation, but upon denaturation the spectrum returned to that of the oxidized form, suggesting that attachment is to an amino acid residue, not to the flavin. 5-(Aminomethyl)-3-(4-cyanophenyl)-2-oxazolidinone inactivates MAO at a rate comparable to or faster than does the corresponding 4-methoxyphenyl analogue, suggesting that there is little or no electronic effect of ring substitution on the rate of inactivation. All of these results support an inactivation mechanism that involves one-electron oxidation of the amine to the amine radical cation, followed by proton removal to give the α radical, which can partition among three pathways (Scheme V): radical combination with an active-site amino acid residue radical to give inactive enzyme, decomposition of the oxazolidinone ring with loss of CO2, and second electron transfer to give the corresponding aldehyde product.

Original languageEnglish (US)
Pages (from-to)9364-9372
Number of pages9
JournalJournal of the American Chemical Society
Volume112
Issue number25
DOIs
StatePublished - Jan 1990

ASJC Scopus subject areas

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

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