The synthesis of lysylfluoromethanes and their properties as inhibitors of trypsin, plasmin and cathepsin B.
The synthesis of two lysylfluoromethanes is described by an extension of the synthesis method of Rauber, Angliker, Walker & Shaw [(1986) Biochem. J. 239, 633-640]. Ala-Phe-Lys-CH2F was found to be an active-centre-directed inhibitor of plasmin and trypsin, as is the corresponding chloromethane. However, the rate of covalent-bond formation is about an order of magnitude lower at 25 degrees C for the fluoro derivative. It was, in addition, an extremely effective inactivator of cathepsin B at pH 5.4 and 6.4. The chemical reactivity of fluoromethanes was compared with that of chloromethanes as alkylators of GSH. At pH 7.4 and 37 degrees C, a fluoromethane has 1/500th the reactivity of a chloromethane. A comparison of the rates of reaction of the fluoromethane with cathepsin B and with GSH at pH 6.4 revealed an enhancement of 10(8)-fold for the alkylation of the enzyme, ascribable largely to a proximity effect.
D000478:Alkylation; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D005978:Glutathione / Q000378:metabolism; D007659:Ketones / Q000494:pharmacology; D007700:Kinetics; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
D004151:Dipeptides; D007659:Ketones; D009842:Oligopeptides; D014361:Trypsin Inhibitors; C052818:benzoylphenylalanyllysine fluoromethane; C052817:alanyl-phenylalanyl-lysine fluoromethane; D005341:Fibrinolysin; D002401:Cathepsin B; D005978:Glutathione