Journal
CHEMMEDCHEM
Volume 5, Issue 9, Pages 1556-1567Publisher
WILEY-BLACKWELL
DOI: 10.1002/cmdc.201000109
Keywords
aryl vinyl sulfones; cathepsins; cysteine proteases; enzymes; medicinal chemistry
Categories
Funding
- ENANTIA
- MCYT [Bio2008-00799]
- MEC [AYA2006-15648-C02-01]
- Generalitat de Catalunya [2009SGR1005]
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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.
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