Author(s)

Brandon D. Fennell

Graduation Year

2011

Date of Thesis Acceptance

Fall 5-6-2011

Major Department or Program

Chemistry

Advisor(s)

Marion Gotz

Abstract

This research investigates the synthesis and kinetic analysis of a series of novel dipeptidyl allyl sulfones functioning as clan CA cysteine protease inhibitors. The structure of the inhibitors consists of a R1-Phe-R2-AS-Ph scaffold where R1 represents either a benzyloxycarbonyl or morpholinocarbonyl group and R2 is either a Phe or Hfe residue. In order to synthesize the inhibitors, the vinyl sulfone analogues were first synthesized and then isomerized to the allyl sulfones using n-butyl lithium and t-butyl hydroperoxide. Sterics, temperature, and base strength were factors which affected the formation of the allyl sulfone moiety and were analyzed in this study. The inhibitors were assayed with three clan CA cysteine proteases, cruzain, cathepsin B, and calpain I, using a fluorogenic assay. It was demonstrated that the stereochemistry of the allyl sulfone plays an important role in the strength of the inhibitor. The most potent inhibitor, (E)-Mu-Phe-Hfe-AS-Ph, displayed 20-fold selectivity for cruzain and had a kobs/[I] of 5800 ± 2000 M-1s-1.

Page Count

54

Subject Headings

Cathepsin B, Cysteine proteinases -- Inhibitors, Chemical kinetics, Protozoan proteins, Stereooisomers, Peroxides -- tert-butylhydroperoxide, Structure-activity relationships (Biochemistry), Calpain, Protease inhibitors, Sulfones, Whitman College 2011 -- Dissertation collection -- Chemistry Department

Permanent URL

http://hdl.handle.net/10349/1007

Document Type

Whitman Community Accessible Thesis

Terms of Use

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

Share

COinS
 

Rights Statement

Rights Statement

In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/
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).