Studies of the synthesis of all stereoisomers of MG-132 proteasome inhibitors in the tumor targeting approach

J Med Chem. 2010 Feb 25;53(4):1509-18. doi: 10.1021/jm901619n.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Chymotrypsin / antagonists & inhibitors
  • Chymotrypsin / metabolism
  • Endopeptidases / metabolism
  • Erythrocytes / drug effects
  • Erythrocytes / enzymology
  • Humans
  • Hydrolysis
  • In Vitro Techniques
  • Leupeptins / chemical synthesis*
  • Leupeptins / chemistry
  • Leupeptins / pharmacology
  • Nitriles / chemical synthesis
  • Nitriles / chemistry
  • Proteasome Inhibitors*
  • Stereoisomerism
  • Trypsin / metabolism


  • Antineoplastic Agents
  • Leupeptins
  • Nitriles
  • Proteasome Inhibitors
  • Endopeptidases
  • Chymotrypsin
  • Trypsin
  • peptidylglutamylpeptide hydrolase
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde