Functionalized depsipeptides, substrates and inhibitors of β-lactamases and DD-peptidases
| Autor: | R. F. Pratt, Y. Xub, D. Cabaret, J. Liu, M. Wakselman |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Substituent Pharmaceutical Science Muramoylpentapeptide Carboxypeptidase beta-Lactams Biochemistry beta-Lactamases Serine Structure-Activity Relationship chemistry.chemical_compound Bacillus cereus Nucleophile Drug Discovery Molecular Biology Binding Sites Molecular Structure biology Aryl Organic Chemistry Leaving group Active site Quinone methide Streptomyces Anti-Bacterial Agents Models Chemical chemistry Electrophile biology.protein Molecular Medicine Peptides beta-Lactamase Inhibitors |
| Zdroj: | Bioorganic & Medicinal Chemistry. 2:757-771 |
| ISSN: | 0968-0896 |
| Popis: | A series of derivatives of phenyl phenylacetylglycinates (aryl phenaceturates) with a carboxylate substituent meta to the oxygen of the phenoxide leaving group and a functionalized methylene group in the ortho- or para-position have been synthesized. These molecules possess a latent o- or p-quinone methide electrophile which could be unmasked during enzymic turnover and could react with an active site nucleophile. This chemistry does seem to occur in solution where a common hydrolysis product, independent of the benzylic leaving group, presumably o- or p-hydroxymethylphenol, was observed. These depsipeptides are substrates of class A and C β-lactamases, particularly of the latter, comparable with the parent m-carboxyphenyl phenaceturate. They also have modest inhibitory activity against these enzymes and against the serine DD-peptidase of Streptomyces R61. The inhibition of a class C β-lactamase was turnover dependent, as expected of mechanism-based inhibitor, but the small leaving group dependence of the inhibition suggested that the quinone methide, if it was in fact responsible for the inhibition, was generated in solution subsequent to release of the product phenol from the active site. |
| Databáze: | OpenAIRE |
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