Document Detail

Synthesis and evaluation of vinyl sulfones as caspase-3 inhibitors. A structure-activity study.
MedLine Citation:
PMID:  20541849     Owner:  NLM     Status:  MEDLINE    
The first structure-activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P(1), as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH=CH-SO(2)Me was the most potent inhibitor of caspase-3 in the series, with a IC(50) of 29 microM and a second-order rate constant of inactivation, k(inact)/K(i), of 1.5 M(-1) s(-1). Computational studies suggest that the second amino acid occupies position S(3) of the enzyme. In addition, Fmoc-Val-Asp-trans-CH=CH-SO(2)Ph was inactive for caspase-7 for the tested concentrations.
Ana S Newton; Paulo M C Glória; Lídia M Gonçalves; Daniel J V A dos Santos; Rui Moreira; Rita C Guedes; Maria M M Santos
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-24
Journal Detail:
Title:  European journal of medicinal chemistry     Volume:  45     ISSN:  1768-3254     ISO Abbreviation:  Eur J Med Chem     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-09     Completed Date:  2010-11-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0420510     Medline TA:  Eur J Med Chem     Country:  France    
Other Details:
Languages:  eng     Pagination:  3858-63     Citation Subset:  IM    
Copyright Information:
2010 Elsevier Masson SAS. All rights reserved.
Medicinal Chemistry, iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019 Lisboa, Portugal.
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MeSH Terms
Caspase 3 / antagonists & inhibitors*,  chemistry
Caspase 7 / antagonists & inhibitors
Enzyme Inhibitors / chemical synthesis,  chemistry*,  pharmacology*
Inhibitory Concentration 50
Models, Molecular
Protein Conformation
Structure-Activity Relationship
Sulfones / chemical synthesis,  chemistry*,  pharmacology*
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Sulfones; 77-77-0/divinyl sulfone; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7

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