Show simple item record

dc.contributor.authorYu, Jianen_US
dc.date.accessioned2014-03-14T20:22:28Z
dc.date.available2014-03-14T20:22:28Z
dc.date.issued1998-08-10en_US
dc.identifier.otheretd-72798-21488en_US
dc.identifier.urihttp://hdl.handle.net/10919/30688
dc.description.abstractThe 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.en_US
dc.publisherVirginia Techen_US
dc.relation.haspartthesis-98-2.pdfen_US
dc.rightsI hereby grant to Virginia Tech or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University Libraries in all forms of media, now or hereafter known. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation.en_US
dc.subjectmonoamine oxidaseen_US
dc.subjecttetrahydropyridineen_US
dc.subjectisotope effecten_US
dc.subjectdeuteriumen_US
dc.subjectchiral auxiliaryen_US
dc.titleSynthesis and mechanistic studies on the monoamine oxidase (MAO) catalyzed oxidation of 1,4-disubstituted-1,2,3,6-tetrahydropyridinesen_US
dc.typeDissertationen_US
dc.contributor.departmentChemistryen_US
dc.description.degreePh. D.en_US
thesis.degree.namePh. D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineChemistryen_US
dc.contributor.committeememberWolfe, James F.en_US
dc.contributor.committeememberCalter, Michael A.en_US
dc.contributor.committeememberMerola, Joseph S.en_US
dc.contributor.committeememberAnderson, Mark R.en_US
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-72798-21488/en_US
dc.date.sdate1998-08-10en_US
dc.date.rdate1998-08-28
dc.date.adate1998-08-28en_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record