Studies of the Synthesis of All Stereoisomers of MG-132 Proteasome Inhibitors in the Tumor Targeting Approach

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 oil the Ugi reaction. Chiral, enantiomerically stable 2-isocyano-4-methyl-pentyl 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 oil 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.