title: A coumarin-labeled vinyl sulfone as tripeptidomimetic activity-based probe for cysteine cathepsins.
abstract: A coumarin-tetrahydroquinoline hydride 8 was synthesized as a chemical tool for fluorescent labeling. The rigidified tricyclic coumarin structure was chosen for its suitable fluorescence properties. The connection of 8 with a vinyl sulfone building block was accomplished by convergent synthesis thereby leading to the coumarin-based, tripeptidomimetic activity-based probe 10, containing a Gly-Phe-Gly motif. Probe 10 was evaluated as inactivator of the therapeutically relevant human cysteine cathepsins S, L, K, and B: it showed particularly strong inactivation of cathepsin S. The detection of recombinant and native cathepsin S was demonstrated by applying 10 to in-gel fluorescence imaging.
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors.forename: Matthias D
authors.initials: MD
authors.lastname: Mertens
authors.forename: Janina
authors.initials: J
authors.lastname: Schmitz
authors.forename: Martin
authors.initials: M
authors.lastname: Horn
authors.forename: Norbert
authors.initials: N
authors.lastname: Furtmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.forename: Michael
authors.initials: M
authors.lastname: Mareš
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002403:Cathepsins / Q000737:chemistry / Q000378:metabolism*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D011804:Quinolines / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry*
chemical_list: D003374:Coumarins; D004151:Dipeptides; D005456:Fluorescent Dyes; D007527:Isoenzymes; D011804:Quinolines; D013450:Sulfones; C000594501:methyl 2-oxo-9-(2-oxo-2-(1-oxo-3-phenyl-1-(3-(phenylsulfonyl)allylamino)propan-2-ylamino)ethyl)-6,7,8,9-tetrahydro-2H-pyrano(3,2-g)quinoline-3-carboxylate; C009873:divinyl sulfone; C030123:coumarin; C542964:1,2,3,4-tetrahydroquinoline; D002403:Cathepsins; C028217:cathepsin S
keywords: activity-based probes; cathepsins; coumarins; fluorescent probes; inhibitors; peptidyl vinyl sulfones