Syntheses of amino nitrones. Potential intramolecular traps for radical intermediates in monoamine oxidase-catalyzed reactions

Boyu Zhong, Xingliang Lu, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Monoamine oxidase (MAO) is a flavin-dependent enzyme that catalyzes the oxidative deamination of a variety of amine neurotransmitters and toxic amines. Although there have been several studies that support the intermediacy of an amine radical cation and an α-radical during enzyme catalysis, there is no direct, i.e. EPR, evidence for these species as they are formed. Amino nitrones have been designed which, upon radical formation would produce an intermediate that is a resonance structure of the corresponding nitroxyl radical, which should be observable by EPR spectroscopy. Syntheses of seven different amino nitrones, three acyclic, and four cyclic analogues were attempted. The protected amino nitrones were stable, but all three of the acyclic amino nitrones were unstable. One of the cyclic analogues was very stable (39), one was stable only in organic solvents (40), one was stable only in aqueous medium below pH 6.5 (41), and the other (42) was stable for just a short time at room temperature, decomposing to a stable free radical. None of these analogues produced a MAO-catalyzed radical, yet 41 is a poor substrate (K(m)=0.2mM; k(cat)=0.034min-1) and 39 is a mixed inhibitor (K(i)=26.5mM). Although this approach does not appear to be applicable to amino nitrones, it should be a valuable approach for other enzymes where radical intermediates are suspected and nonamine nitrones can be utilized. Copyright (C) 1998 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)2405-2419
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume6
Issue number12
DOIs
StatePublished - Dec 1998

Keywords

  • Amino nitrones
  • Enzyme mechanism
  • Monoamine oxidase
  • Radical intermediate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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