Graduation Year


Date of Thesis Acceptance

Spring 5-13-2015

Major Department or Program



Marion Gotz


The proteasome is a large, multicatalytic protease found in all forms of life. The proteasome is instrumental in the regulation of many cellular pathways such as cell cycle arrest and cell proliferation. For this reason, proteasome inhibitors are of interest in drug development because of their ability to regulate the asynchronous cell cycles of cancers. In particular, multiple myeloma has been shown to be receptive to treatment with proteasome inhibitors. In this study, two novel macrocyclic peptidyl aldehyde proteasome inhibitors 11 and 12 are reported. The design of 11 and 12 was bioinspired by the natural product TMC-95A, a macrocyclic tripeptide shown to potently and selectively inhibit the proteasome. Compounds 11 and 12 were designed to test the effects of the peptide macrocycle on inhibitory strength and specificity. Both inhibitors were identical in sequence, however 12 incorporated a biaryl ether linkage to mimic the macrocyclic structure of TMC-95. Additionally, both inhibitors incorporated a C-terminal aldehyde designed to covalently bind the proteasome’s catalytic threonine residue and hydrophobic side chains to target the chymotrypsin-like activity of the proteasome. In vitro testing of both inhibitors revealed them to be potent and specific inhibitors of the chymotrypsin-like activity of the proteasome (11, Ki = 33 nM, 12, Ki = 76 nM). It was found that there was no trend to suggest that the peptide macrocycle conferred increased specificity or binding. Ex vivo assays for 12 showed it to be metabolically stable, readily taken up by HeLa cells, and perform on par with the well characterized proteasome inhibitor MG-132. Finally, QM/MM studies suggested that the oxindole moiety found in the macrocycle of TMC-95A is essential for specificity for the chymotrypsin-like active site of the proteasome.

Page Count


Subject Headings

In Vitro Techniques, Synthesis -- TMC-95A, Cells -- Chemistry, Proteolytic enzymes -- Analysis, Proteolysis, Protease inhibitors, Whitman College -- Dissertation collection 2015 -- Chemistry Department

Permanent URL

Document Type

Whitman Community Accessible Thesis

Terms of Use

If you have questions about permitted uses of this content, please contact the ARMINDA administrator



Rights Statement

Rights Statement

In Copyright. URI:
This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).