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Synthesis of macrocyclic, potential protease inhibitors using a generic scaffold

Lookup NU author(s): Dr Estelle Dumez, Professor Richard Jackson

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Abstract

A generic macrocyclic peptide structure 2 was designed as a potential inhibitor of a range of proteinases, by using as a basis for the design the known structures of a series of enzyme-inhibitor complexes. The macrocyclic nature of the target 2 was chosen so as to reduce the entropic advantage in the hydrolytic enzymatic step, and thereby to inhibit the function of the enzyme. The nature of the linking group was identified as a benzoxazole by molecular modeling, so as to preserve the recognized conformation of the peptide chain. The specificity of the potential inhibitor was tuned by variation of the Pi group (by incorporating phenylalanine, aspartic acid, or lysine), to allow recognition by different enzyme classes. The targets were prepared from the bis-amino acid derivative 5, itself prepared using the Pd-catalyzed coupling of an organozinc reagent with the iodobenzothiazole 7 and subsequent macrocyclization of the open-chain derivatives 22-24 using HATU. None of the macrocylic compounds 25, 28-30, and 32 inhibited their target enzymes. NMR and MS studies on the interaction of macrocycle 29 and chymotrypsin established that compound 29 was in fact a substrate of the enzyme. This result indicated that while the design had been partially successful in identifying a compound that bound, the reduction in entropic advantage due to its macrocyclic nature was not sufficient to allow 29 to act as an inhibitor.


Publication metadata

Author(s): Dumez E, Snaith JS, Jackson RFW, McElroy AB, Overington J, Wythes MJ, Withka JM, McLellan TJ

Publication type: Article

Publication status: Published

Journal: Journal of Organic Chemistry

Year: 2002

Volume: 67

Issue: 14

Pages: 4882-4892

ISSN (print):

ISSN (electronic): 1520-6904

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/jo025615o

DOI: 10.1021/jo025615o


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