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 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.
Mroczkiewicz
Michał
M
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland.
Winkler
Katarzyna
K
Nowis
Dominika
D
Placha
Grzegorz
G
Golab
Jakub
J
Ostaszewski
Ryszard
R
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007976:Leupeptins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry; D061988:Proteasome Inhibitors; D013237:Stereoisomerism; D014357:Trypsin / Q000378:metabolism
D000970:Antineoplastic Agents; D007976:Leupeptins; D009570:Nitriles; D061988:Proteasome Inhibitors; D010450:Endopeptidases; D002918:Chymotrypsin; D014357:Trypsin; C114177:peptidylglutamylpeptide hydrolase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde