Synthesis, Calpain Inhibitory Activity, and Cytotoxicity of P2-Substituted Proline and Thiaproline Peptidyl Aldehydes and Peptidyl α-Ketoamides

• Published in: Journal of medicinal chemistry Vol. 49; no. 17; pp. 5282 - 5290
• Main Authors: Korukonda, Rajani, Guan, Na, Dalton, James T, Liu, Jiuyu, Donkor, Isaac O
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 24.08.2006
• Subjects: Aldehydes - chemical synthesis; Aldehydes - chemistry; Aldehydes - pharmacology; Antineoplastic agents; Biological and medical sciences; Calpain - antagonists & inhibitors; Cathepsin B - antagonists & inhibitors; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; General aspects; HeLa Cells; Humans; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Proline - chemistry; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Stereoisomerism; Structure-Activity Relationship; Sulfones - chemistry; Sulfones - pharmacology; Thiazoles - chemistry; Thiazolidines; Antineoplastic agent; Human; Solid tumor; Ketoamide; Peptides; Enzyme; Cysteine endopeptidases; Enzyme inhibitor; Calpain; Cytotoxicity; Malignant tumor; Uterine cervix; Aldehyde; In vitro; Hela cell line; Peptidases; Cell line; Structure activity relation; T-Lymphocyte; Hydrolases; Chemical synthesis; Prostate; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050849w

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.