Novel peptidyl aryl vinyl sulfones as highly potent and selective inhibitors of cathepsins L and B.
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.
Mendieta
Laura
L
Institute for Research in Biomedicine of Barcelona, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain.
Picó
Anna
A
Tarragó
Teresa
T
Teixidó
Meritxell
M
Castillo
Marcos
M
Rafecas
Llorenç
L
Moyano
Albert
A
Giralt
Ernest
E
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
D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D013450:Sulfones; D002401:Cathepsin B; D056668:Cathepsin L