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

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dc.contributor.advisor Dunlap, Norma Harmon, Chelsea Harmon 2017-05-26T18:00:51Z 2017-05-26T18:00:51Z 2017-06-01
dc.description.abstract Belactosin 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.publisher Middle Tennessee State University
dc.subject Belactosin A
dc.subject Beta-lactam
dc.subject Cyclopropyl
dc.subject Peptidomimetic
dc.subject Proteasome
dc.title Synthesis of Beta-Lactam Belactosin A Analogs as Potential 20S Proteasome Inhibitors
dc.type Thesis
dc.contributor.committeemember Bicker, Kevin
dc.contributor.committeemember Miller, Justin
dc.thesis.degreelevel Masters
dc.thesis.degreegrantor Middle Tennessee State University
dc.subject.umi Chemistry
dc.subject.umi Organic chemistry M.S.
dc.contributor.department Chemistry en_US

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