| Abstract
| - A generic macrocyclic peptide structure 2 was designed as a potential inhibitor of a range ofproteinases, by using as a basis for the design the known structures of a series of enzyme−inhibitorcomplexes. The macrocyclic nature of the target 2 was chosen so as to reduce the entropic advantagein the hydrolytic enzymatic step, and thereby to inhibit the function of the enzyme. The nature ofthe linking group was identified as a benzoxazole by molecular modeling, so as to preserve therecognized conformation of the peptide chain. The specificity of the potential inhibitor was tunedby variation of the P1 group (by incorporating phenylalanine, aspartic acid, or lysine), to allowrecognition by different enzyme classes. The targets were prepared from the bis-amino acidderivative 5, itself prepared using the Pd-catalyzed coupling of an organozinc reagent with theiodobenzothiazole 7 and subsequent macrocyclization of the open-chain derivatives 22−24 usingHATU. None of the macrocylic compounds 25, 28−30, and 32 inhibited their target enzymes. NMRand MS studies on the interaction of macrocycle 29 and chymotrypsin established that compound29 was in fact a substrate of the enzyme. This result indicated that while the design had beenpartially successful in identifying a compound that bound, the reduction in entropic advantagedue to its macrocyclic nature was not sufficient to allow 29 to act as an inhibitor.
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