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|Title:||N-Linked Peptidoresorcarene-Based Receptors as Noncompetitive Inhibitors for alpha-Chymotrypsin||Authors:||D'Acquarica, I
Delle Monache, G
|Issue Date:||2011||Project:||None||Journal:||JOURNAL OF ORGANIC CHEMISTRY||Abstract:||
This paper deals with the design, synthesis, andevaluation of a new series of receptors for protein surfacerecognition. The design of these agents is based around theattachment of four constrained dipeptide chains onto a centralresorcarene scaffold. By varying the sequence, nature, andstereochemistry of the chains we prepared anionically functionalizedN-linked peptidoresorcarenes 12, 13, and 17 by Pd/C-catalyzed hydrogenation of the corresponding benzyl esters10, 11, and 16. From this family of receptors we have identifiednoncompetitive inhibitors of R-chymotrypsin (ChT), whichfunction by binding to the surface of the enzyme in theneighborhood of the active site cleft (Ki values ranging from12.4 ( 5.1 μM for free carboxylic acid (þ)-12b to 0.76 (0.14 μM for benzyl ester ()-16a). For anionically functionalizedreceptors 12, 13, and 17 the ChT inhibition is basedessentially on electrostatic interaction, and the bound enzymecan be released from the resorcarene surface by increasing the ionic strength, with its activity almost completely restored. Forreceptors with terminal benzyl ester groups (10 and 16) a hydrophobic network can be suggested.
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