jm901619n_si_001.pdf (72.68 kB)
Studies of the Synthesis of All Stereoisomers of MG-132 Proteasome Inhibitors in the Tumor Targeting Approach
journal contributionposted on 2010-02-25, 00:00 authored by Michał Mroczkiewicz, Katarzyna Winkler, Dominika Nowis, Grzegorz Placha, Jakub Golab, Ryszard Ostaszewski
MG-132 is a tripeptide aldehyde (Z-l-leu-l-leu-l-leu-H, 2) proteasome inhibitor that exerts antitumor activity and enhances cytostatic/cytotoxic effects of chemo- and radiotherapy. Because of a troublesome synthesis of tripeptides with a non-natural configuration and modified side chains of amino acids, only two stereoisomers of MG-132 have been reported. Here, we propose a new approach to the synthesis of tripeptide aldehydes based on the Ugi reaction. Chiral, enantiomerically stable 2-isocyano-4-methylpentyl acetates were used as substrates for Ugi reaction resulting in a formation of tripeptide skeletons. Further functionalization of the obtained products led to a synthesis of tripeptide aldehydes. All stereoisomers of MG-132 were synthesized and studied as potential inhibitors of chymotrypsin-like, trypsin-like, and peptidylglutamyl peptide hydrolyzing activities of proteasome. These studies demonstrated the influence of absolute configuration of chiral aldehydes on the cytostatic/cytotoxic effects of the synthesized compounds and revealed that only (S,R,S)-(−)-2 stereoisomer is a more potent proteasome inhibitor than MG-132.