Synthesis of Beta-Lactam Belactosin A Analogs as Potential 20S Proteasome Inhibitors

dc.contributor.advisorDunlap, Norma
dc.contributor.authorHarmon, Chelsea Harmon
dc.contributor.committeememberBicker, Kevin
dc.contributor.committeememberMiller, Justin
dc.contributor.departmentChemistryen_US
dc.date.accessioned2017-05-26T18:00:51Z
dc.date.available2017-05-26T18:00:51Z
dc.date.issued2017-06-01
dc.description.abstractBelactosin A is a naturally occurring proteasome inhibitor with potent anti-tumor activity, however it does not possess the properties necessary to be used clinically. Like other proteasome inhibitors, such as carfilzomib and bortezomib, which are currently used to treat myelomas, belactosin A exhibits a peptidomimetic backbone with a serine trap at the C-terminal end. Key structural features of the natural product include a cyclopropane ring and a terminal -lactone as the serine trap. While several syntheses of belactosin A have been reported, only a few analogs have been prepared, all of which maintained the -lactone as the serine trap. Though -lactams are classic serine traps, only two have been reported as proteasome inhibitors. The synthesis of novel -lactam analogs of belactosin A is reported here, with the key step being coupling of cyclopropyl peptidomimetics to -lactams. The use of phenylalanine, leucine, and valine as starting materials leads to benzyl, isobutyl, and isopropyl analogs of the natural product. Attempts were made to optimize functionalization of the cyclopropyl backbones for coupling to the -lactams, which lead to the proposal of a modified synthetic route to achieve the proposed analogs.
dc.description.degreeM.S.
dc.identifier.urihttp://jewlscholar.mtsu.edu/xmlui/handle/mtsu/5311
dc.publisherMiddle Tennessee State University
dc.subjectBelactosin A
dc.subjectBeta-lactam
dc.subjectCyclopropyl
dc.subjectPeptidomimetic
dc.subjectProteasome
dc.subject.umiChemistry
dc.subject.umiOrganic chemistry
dc.thesis.degreegrantorMiddle Tennessee State University
dc.thesis.degreelevelMasters
dc.titleSynthesis of Beta-Lactam Belactosin A Analogs as Potential 20S Proteasome Inhibitors
dc.typeThesis

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