title: Novel peptidyl aryl vinyl sulfones as highly potent and selective inhibitors of cathepsins L and B.
abstract: Herein we present the design, synthesis, and evaluation of a structurally novel library of 20 peptidyl 3-aryl vinyl sulfones as inhibitors of cathepsins L and B. The building blocks, described here for the first time, were synthesized in a highly efficient and enantioselective manner, starting from 3-aryl-substituted allyl alcohols. The corresponding vinyl sulfones were prepared by a new approach, based on a combination of solid-phase peptide synthesis using the Fmoc/tBu strategy, followed by solution-phase coupling to the corresponding (R)-3-amino-3-aryl vinyl sulfones as trifluoroacetate salts. The inhibitory activity of the resulting compounds against cathepsins L and B was evaluated, and the compound exhibiting the best activity was selected for enzymatic characterization. Finally, docking studies were performed in order to identify key structural features of the aryl substituent.
authors.affiliation: Institute for Research in Biomedicine of Barcelona, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Mendieta
authors.forename: Anna
authors.initials: A
authors.lastname: Picó
authors.forename: Teresa
authors.initials: T
authors.lastname: Tarragó
authors.forename: Meritxell
authors.initials: M
authors.lastname: Teixidó
authors.forename: Marcos
authors.initials: M
authors.lastname: Castillo
authors.forename: Llorenç
authors.initials: L
authors.lastname: Rafecas
authors.forename: Albert
authors.initials: A
authors.lastname: Moyano
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
mesh_terms: D001665:Binding Sites; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D013450:Sulfones; D002401:Cathepsin B; D056668:Cathepsin L