Acid-sensitive latent inhibitors for proteolytic enzymes: synthesis and characterization.
The reaction between peptide aldehydes and acylhydrazones affords derivatives that represent potential prodrugs for selective inhibition of lysosomal enzymes. BzPheal = Ala, obtained from the reaction between N-benzoyl-L-phenylalaninal and N-acetyl-L-alanine hydrazide, has been most carefully studied. When BzPheal = Ala is introduced into ongoing reactions catalyzed by alpha-chymotrypsin or papain, the rate of these reactions diminishes more rapidly with time than do those of controls lacking BzPheal = Ala. Furthermore, the disparity between run and control is much greater at pH 5 than at pH 7. The extent of inhibition (defined as explained in the text) at pH 5 can exceed that at pH 7 by 25-40-fold. The data are quantitatively explained by a reaction scheme that recognizes three important properties of BzPheal = Ala: (1) It undergoes hydrolysis at pH 5-7 to regenerate N-benzoyl-L-phenylalaninal; (2) the aldehyde thus liberated is a far more potent inhibitor for serine or cysteine proteases than is BzPheal = Ala; and (3) the rate constant for hydrolysis of BzPheal = Ala at pH 5 greatly exceeds that at pH 7.
Silver
M S
MS
Department of Chemistry, Amherst College, Massachusetts 01002.
Haskell
J H
JH
D000447:Aldehydes; D055598:Chemical Phenomena; D002621:Chemistry; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006835:Hydrazones; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008247:Lysosomes / Q000201:enzymology; D010206:Papain / Q000037:antagonists & inhibitors / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
D000447:Aldehydes; D006835:Hydrazones; D011355:Prodrugs; D011480:Protease Inhibitors; D010649:Phenylalanine; C053764:benzoylphenylalanine; D002918:Chymotrypsin; D010206:Papain