title: Synthesis, calpain inhibitory activity, and cytotoxicity of P2-substituted proline and thiaproline peptidyl aldehydes and peptidyl alpha-ketoamides.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Rajani
authors.initials: R
authors.lastname: Korukonda
authors.forename: Na
authors.initials: N
authors.lastname: Guan
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Jiuyu
authors.initials: J
authors.lastname: Liu
authors.forename: Isaac O
authors.initials: IO
authors.lastname: Donkor
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D011392:Proline / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry*; D053778:Thiazolidines
chemical_list: C513860:1-(4-iodophenylsulfonyl)-N-(1-oxo-3-phenylpropan-2-yl)pyrrolidine-2-carboxamide; C513859:1-(4-nitrophenylsulfonyl)-N-(1-oxo-3-phenylpropan-2-yl)pyrrolidine-2-carboxamide; D000447:Aldehydes; D011760:Pyrrolidinones; D013450:Sulfones; D013844:Thiazoles; D053778:Thiazolidines; D011392:Proline; C003438:thiazolidine-4-carboxylic acid; D002154:Calpain; C449002:mu-calpain; D002401:Cathepsin B