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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.
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
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