title: Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors.
abstract: This research investigates the synthesis and inhibitory potency of a series of novel dipeptidyl allyl sulfones as clan CA cysteine protease inhibitors. The structure of the inhibitors consists of a R(1)-Phe-R(2)-AS-Ph scaffold (AS = allyl sulfone). R(1) was varied with benzyloxycarbonyl, morpholinocarbonyl, or N-methylpiperazinocarbonyl substituents. R(2) was varied with either Phe of Hfe residues. Synthesis involved preparation of vinyl sulfone analogues followed by isomerization to allyl sulfones using n-butyl lithium and t-butyl hydroperoxide. Sterics, temperature and base strength were all factors that affected the formation and stereochemistry of the allyl sulfone moiety. The inhibitors were assayed with three clan CA cysteine proteases (cruzain, cathepsin B and calpain I) as well as one serine protease (trypsin). The most potent inhibitor, (E)-Mu-Phe-Hfe-AS-Ph, displayed at least 10-fold selectivity for cruzain over clan CA cysteine proteases cathepsin B and calpain I with a (kobs)/[I] of 6080 ± 1390 M(-1)s(-1).
authors.affiliation: Department of Chemistry, Whitman College, WA 99362, USA.
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Fennell
authors.forename: Julia M
authors.initials: JM
authors.lastname: Warren
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Chung
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Main
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Arend
authors.forename: Anna
authors.initials: A
authors.lastname: Tochowicz
authors.forename: Marion G
authors.initials: MG
authors.lastname: Götz
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D060326:Chemistry Techniques, Synthetic / Q000379:methods; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry*; D013696:Temperature; D020122:tert-Butylhydroperoxide / Q000737:chemistry
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D013450:Sulfones; C009873:divinyl sulfone; D020122:tert-Butylhydroperoxide; D002154:Calpain; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; D002401:Cathepsin B