Synthesis, Calpain Inhibitory Activity, and Cytotoxicity of P2-Substituted Proline and Thiaproline Peptidyl Aldehydes and Peptidyl α-Ketoamides
Calpain is a cytosolic cysteine endopeptidase that has been implicated in a number of disorders including cancer. We have synthesized and studied the μ-calpain inhibitory activity and cytotoxicity of peptidyl aldehydes and peptidyl α-ketoamides with N-substituted d-proline or l-thiaproline residues...
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Published in | Journal of medicinal chemistry Vol. 49; no. 17; pp. 5282 - 5290 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Washington, DC
American Chemical Society
24.08.2006
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Subjects | |
Online Access | Get full text |
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Summary: | Calpain is a cytosolic cysteine endopeptidase that has been implicated in a number of disorders including cancer. We have synthesized and studied the μ-calpain inhibitory activity and cytotoxicity of peptidyl aldehydes and peptidyl α-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 μ-calpain with K i values of 0.02 μM and 0.03 μM, respectively, and displayed over 180-fold (1j) and 130-fold (1n) greater affinity for μ-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 μ-calpain inhibition. |
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Bibliography: | ark:/67375/TPS-R7LRJV9J-5 istex:B6D7A765D9825AB05BA10826AE85F61C7261186F ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm050849w |