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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
17
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pubmed:dateCreated |
2006-8-17
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pubmed:abstractText |
Calpain is a cytosolic cysteine endopeptidase that has been implicated in a number of disorders including cancer. We have synthesized and studied the mu-calpain inhibitory activity and cytotoxicity of peptidyl aldehydes and peptidyl alpha-ketoamides with N-substituted D-proline or L-thiaproline residues at the P2-postion. The most potent and most selective members of the series were (R)-1-(4-nitrophenylsulfonyl)-N-((R,S)-1-oxo-3-phenylpropan-2-yl)pyrrolidine-2-carboxamide (1j) and (R)-1-(4-iodophenylsulfonyl)-N-((R,S)-1-oxo-3-phenylpropan-2-yl)pyrrolidine-2-carboxamide (1n). The compounds inhibited mu-calpain with Ki values of 0.02 microM and 0.03 microM, respectively, and displayed over 180-fold (1j) and 130-fold (1n) greater affinity for mu-calpain compared to cathepsin B. The cytotoxic effect of the compounds was evaluated in two leukemia cell lines (Daudi and Jurkat) and three solid tumor cell lines (DU-145, PC-3, and HeLa). Generally the compounds were modestly cytotoxic and displayed no correlation between the cytotoxic activity and mu-calpain inhibition.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
24
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5282-90
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:16913717-Aldehydes,
pubmed-meshheading:16913717-Calpain,
pubmed-meshheading:16913717-Cathepsin B,
pubmed-meshheading:16913717-Cell Line, Tumor,
pubmed-meshheading:16913717-Cell Proliferation,
pubmed-meshheading:16913717-Drug Screening Assays, Antitumor,
pubmed-meshheading:16913717-Enzyme Activation,
pubmed-meshheading:16913717-HeLa Cells,
pubmed-meshheading:16913717-Humans,
pubmed-meshheading:16913717-Molecular Structure,
pubmed-meshheading:16913717-Proline,
pubmed-meshheading:16913717-Pyrrolidinones,
pubmed-meshheading:16913717-Stereoisomerism,
pubmed-meshheading:16913717-Structure-Activity Relationship,
pubmed-meshheading:16913717-Sulfones,
pubmed-meshheading:16913717-Thiazoles,
pubmed-meshheading:16913717-Thiazolidines
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pubmed:year |
2006
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pubmed:articleTitle |
Synthesis, calpain inhibitory activity, and cytotoxicity of P2-substituted proline and thiaproline peptidyl aldehydes and peptidyl alpha-ketoamides.
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pubmed:affiliation |
Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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