Synthesis and evaluation of novel dipeptidyl benzoyloxymethyl ketones as caspase inhibitors

• Published in: Biochemical and biophysical research communications Vol. 336; no. 2; pp. 397 - 400
• Main Authors: Nedev, Hinyu N., Klaiman, Guy, LeBlanc, Andrea, Saragovi, H. Uri
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.10.2005
• Subjects: Benzoyloxymethyl ketones; Caspase Inhibitors; Drug design; Enzyme Inhibitors - analysis; Enzyme Inhibitors - chemistry; Ketones - analysis; Ketones - chemistry; Peptides; Synthesis; Drug design; Synthesis; Caspase inhibitors; Peptides; Benzoyloxymethyl ketones
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.08.098

We describe novel peptide-based caspase inhibitors. Potent and comparatively selective compounds containing a dipeptide scaffold and a substituted oxymethyl ketone as a warhead were developed. The newly synthesized compounds were tested for inhibition in in vitro enzymatic assays of caspases-1, -3, -6, -8, and -9. The benzyloxycarbonyl-phenylglycyl-aspartyl benzoyloxymethyl ketone (Z-Phg-Asp-CH 2OCO-Ph, coded as HU44) was the most potent inhibitor of caspase-1 and caspase-3. Of several analogs of HU44 that were made, the β-Asp methyl ester ( 2) is an effective inhibitor against caspase-3 and caspase-8, and less effective against caspase-1. These compounds did not inhibit caspase-6 and caspase-9 significantly.