title: Synthesis and evaluation of novel dipeptidyl benzoyloxymethyl ketones as caspase inhibitors.
abstract: 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-CH2OCO-Ph, coded as HU44) was the most potent inhibitor of caspase-1 and caspase-3. Of several analogs of HU44 that were made, the beta-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.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Cote St. Catherine, F223 Montreal, Que., Canada H3T 1E2.
authors.forename: Hinyu N
authors.initials: HN
authors.lastname: Nedev
authors.forename: Guy
authors.initials: G
authors.lastname: Klaiman
authors.forename: Andrea
authors.initials: A
authors.lastname: LeBlanc
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
mesh_terms: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry; D007659:Ketones / Q000032:analysis* / Q000737:chemistry*
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007659:Ketones