Novel Peptidyl Aryl Vinyl Sulfones as Highly Potent and Selective Inhibitors of Cathepsins L and B

✍ Scribed by Laura Mendieta; Anna Picó; Teresa Tarragó; Meritxell Teixidó; Marcos Castillo; Llorenç Rafecas; Albert Moyano; Ernest Giralt

• Book ID: 102806232
• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 995 KB
• Volume: 5
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.201000109

✦ Synopsis

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/t__Bu 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.