Synthesis of histidine-containing dipeptide affinity-labelling agents. Relative inactivation rates of cathepsins B and L.
Peptidyl diazomethyl ketones and fluoromethyl ketones containing histidine in the C-terminal position were synthesized to determine their properties as proteinase inactivators. These were examined chiefly with derivatives of Z-Ala-His. The protection of histidine during conversion of the C-terminal residue to the diazomethyl ketone required unblocking conditions which avoid acid due to the lability of this function. This was achievable with a Cbz-imidazole derivative since aminolysis provided deblocking without disturbance of the diazomethyl ketone function. In the case of the fluoromethyl ketone synthesis using fluoroacetic anhydride (Dakin-West procedure), the desired product could be isolated without ring blocking. The Z-Ala-His products showed enhanced selectivity for inactivation of cathepsin B over L when compared to analogous dipeptide inhibitors.
Angliker
H
H
Friedrich Miescher Institute, Basel, Switzerland.
Zumbrunn
A
A
Shaw
E
E
D000345:Affinity Labels / Q000737:chemistry*; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases; D004151:Dipeptides / Q000737:chemistry*; D010450:Endopeptidases; D006639:Histidine / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis*
D000345:Affinity Labels; D004151:Dipeptides; D011480:Protease Inhibitors; D006639:Histidine; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L