Title page for ETD etd-72798-21488

Type of Document Dissertation
Author Yu, Jian
Author's Email Address jyu@vt.edu
URN etd-72798-21488
Title Synthesis and mechanistic studies on the monoamine oxidase (MAO) catalyzed oxidation of 1,4-disubstituted-1,2,3,6-tetrahydropyridines
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Anderson, Mark R. Committee Member
Calter, Michael A. Committee Member
Merola, Joseph S. Committee Member
Wolfe, James F. Committee Member
  • monoamine oxidase
  • tetrahydropyridine
  • isotope effect
  • deuterium
  • chiral auxiliary
Date of Defense 1998-08-10
Availability unrestricted
The parkinsonian inducing drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated in a reaction catalyzed by the flavoenzyme monoamine oxidase B (MAO-B) to form the corresponding dihydropyridinium (MPDP+) subsequently pyridinium (MPP+) metabolites.

As part of our ongoing studies to characterize the structural features responsible for this unexpected biotransformation, we have synthesized and examined the MAO-B substrate properties of a variety of MPTP analogs bearing various heteroaryl groups at the 4-position of the tetrahydropyridinyl ring. The results of these SAR studies indicate that electronic features, steric features and polar interactions can contribute to the substrate activities.

Additionally, isotope effects have been examined to investigate the mechanism and stereoselectivity of the MAO-B catalytic pathway. The synthesis and characterization of regio and stereoselectively deuterated MPTP analogs have been achieved. The results indicate that the catalytic step occurs exclusively at the allylic C-6 position and is rate-determining for both good and poor substrates. The two enantiomers of MPTP bearing a deuterium atom at C-6 have been prepared via chiral aminooxazolinyl derivatives and have been characterized by 2H NMR in a chiral liquid crystal matrix. These enantiomers were used to determine the selectivity of the MAO-B catalyzed a C-H bond cleavage reaction leading to the dihydropyridinium metabolite MPDP+.

Some of the cyclopropyl analogs of MPTP have also been synthesized as the potential inhibitors.

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