Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: SAR of the N-protecting group

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 21; pp. 5295 - 5300
• Main Authors: SUI XIONG CAI, LUFENG GUAN, SHAOJUAN JIA, YAN WANG, WU YANG, TSENG, Ben, DREWE, John
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.11.2004
• Subjects: Amino Acid Chloromethyl Ketones - chemical synthesis; Amino Acid Chloromethyl Ketones - chemistry; Amino Acid Chloromethyl Ketones - pharmacology; Analytical, structural and metabolic biochemistry; Animals; Apoptosis - drug effects; Biological and medical sciences; Caspase 3; Caspase Inhibitors; Caspases - metabolism; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; HeLa Cells; Humans; Hydrolases; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacology; Liver - cytology; Liver - drug effects; Liver - enzymology; Medical sciences; Mice; Miscellaneous; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Structure-Activity Relationship; Survival Rate; Peptides; Hepatoprotector; Liver; Selectivity; Prevention; Hepatocyte; Structure activity relation; Chemical synthesis; Protecting group; Cell permeability; Enzyme; Rodentia; Caspase; Enzyme inhibitor; Haloketone; Peptidases; Vertebrata; Mammalia; Aminoketone; Cytoprotector; Mouse; Cell death; Animal; Dipeptides; Hydrolases; Fluorine Organic compounds; Apoptosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.08.027

This article describes the synthesis and biological evaluation of a group of N-protected Val-Asp-fmk as caspase inhibitors. The protecting group was found to contribute to caspase-3 inhibiting activity, and compounds with a large group such as Cbz are more active than compounds with a small group such as Ac. Compounds with more hydrophobic protecting groups were found to be more active in cell apoptosis protection assays, probably due to increased cell permeability. MX1122, 2,4-di-Cl-Cbz-Val-Asp-fmk, is identified as a potent broad-spectrum caspase inhibitor and is selective for caspases versus other proteases, with good activity in the cell apoptosis protection assays as well as good efficacy in the mouse liver apoptosis model.