Bivalent inhibitors of the proteasome

摘要

A bivalent proteasome inhibitor of the general formula I X-CH(R1)-NH-ÄPÜn-Y-Z-Y'-ÄP'Üm-NH-CH(R1')-X' wherein X and X' are identical or different and are groups selected from aldehyde, boronic acid, boronic acid ester, ketoaldehyde, ketoester, ketoamide, chloromethylketone, trifluoromethylketone, diazomethane; R1 and R1' are identical or different and correspond to the specificity of the S1 enzyme subsite for chymotrypsin- or trypsin-like or PGPH activity of the proteasome, selected from hydrophobic side chains of L- or D-natural and -unnatural amino acids, or amino-, guanido-, amidino-alkyl- or cycloalkyl-, alkaryl-, aralkyl residues and carboxy-alkyl- or aryl- or alkaryl- or aralkyl residues; P and P' are identical or different and correspond to the P2 to P7 substrate positions and are natural or unnatural L- or D-amino acids with hydrophobic or hydrophylic or charged side chains; m and n are identical or different and are 0, 1, 2, 3, 4, 5 or 6; Y and Y' are identical or different and correspond to the formula CO-(A)-(B) where (A) is an alkyl, alkenyl, cycloalkyl, alkaryl, aralkyl or heteroaromatic group and (B) is CO or NH or omitted; and Z is O-CH2-CH2-(O-CH2-CH2)n-O, OC-CH2-(O-CH2-CH2)n-1-O-CH2-CO or NH-CH2-CH2-(O-CH2-CH2)n-NH with n varying from 4 to 50 has interesting properties for various drug applications.