Author(s)

Haya Jamali

Graduation Year

2012

Date of Thesis Acceptance

Spring 5-9-2012

Major Department or Program

Chemistry

Advisor(s)

Marion Gotz

Abstract


Proteases are enzymes that cleave pep tide bonds. One such protease is the 20S proteasome, a ubiquitous complex with a threonine - containing active site. This barrel - shaped proteasome has three distinct binding activities, chymotrypsin - like, trypsin - like, and PGPH that are specific for certain substrates. Inhibition of these binding sites of the 20S proteasome confers one method of cancer therapy. This research explores the synthesis of macrocyclic bimodal inhibitors modeled after the natural product TMC - 95A, which inhibits the proteasome by a h ydrogen - bonding network. Our inhibitors additionally contain a functional group that reacts with the catalytic nucleophile of the enzyme. The synthetic strategy consists of preparation of a tripeptide by solid phase synthesis followed by N - terminal couplin g of a non - natural phenylalanine analog, which is synthesized starting from a benzene derivative. The first of these inhibitors has been assessed via steady - state kinetics. The dissociation constant K i was determined to be 1.6 nM for the chymotrypsin - like activity of the 20S rabbit proteasome, followed by 13 nM and 3.5 nM for the trypsin and PGPH activity, respectively. This compound successfully inhibits the proteasome, which is promising for the other inhibitors that have been synthesized but not yet eval uated.

Page Count

49

Subject Headings

Protease inhibitors

Permanent URL

http://hdl.handle.net/10349/1129

Document Type

Public Accessible Thesis

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Included in

Chemistry Commons

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