Chymotrypsin mimic compounds

Affinity labels are molecules that are structurally similar to the substrate for the enzyme that covalently modify active site residues. They are thus more specific for the enzyme active site than are group-specific reagents. Tosyl-l-phenylalanine chloromethyl ketone (TPCK) is a substrate analog for chymotrypsin (Figure 8.21). TPCK binds at the active site and then reacts irreversibly with a histidine residue at that site, inhibiting the enzyme. The compound 3-bromoacetol is an affinity label for the enzyme triose phosphate isomerase (TIM). It mimics the normal substrate, dihydroxyacetone phosphate, by binding at the active site then it covalently modifies the enzyme such that the enzyme is irreversibly inhibited (Figure 8.22). 

Peptide-based polymers 62, containing imidazole, carboxyl, and hydroxymethyl functionalities, have been prepared from optically active 50d and tested as mimics of enzymes, such as chymotrypsin, which have the same functionalities (Scheme 41) [70]. These polymers exhibit markedly higher activities than the corresponding low molecular weight compounds in the hydrolysis of nitrophenyl and dinitrophenyl esters. Increased activities were... 

As mentioned in Volume 13 of these Reports, 4-oxoazetidin-2-yl phosphonates and phosphinates (19) can be prepared by Arbusov-like reactions between P compounds and 4-acetoxyazetidin-2-one (20). Acid hydrolysis of (19) yields phosphono- and phosphino-aspartic acids (21) which can be converted into peptides with antibacterial activity. Diastereomeric mixtures of phosphono-dipeptides, which can be prepared from racemic dialkyl 1 -aminoalkylphosphonates, can be separated by ion-exchange chromatography. It appears that it is easier to synthesize phosphonodipeptides from these phosphonates as their P-dialkyl esters rather than as the free phosphonic acids. Phosphonic acid analogues of A-Cbz-alanine and -phenylalanine can be converted into ester and amide fluoridates, e.g., (22, R = OMe or NHCHMeg). These fluoridates are the most potent inhibitors of elastase and chymotrypsin yet reported and seem to mimic the natural substrates of these enzymes. ... 

Cram s group, like that of Lehn, is attempting to imitate enzyme catalysis via kinetic acceleration through host-guest complexation. A series of transacylase mimics have been synthesized [44] which contain the complexing site, the proton transfer catalyst and the nucleophile found in the chymotrypsin active site. Relatively rapid rates of acylation were observed. It is obvious, however, that additional information will have to be acquired and more model compounds synthesized before the mode of action of an enzyme such as chymotrypsin can be clarified. 

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