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Biomimetic Hydrolysis of Penicillin G Catalyzed by Dinuclear Zinc(II) Complexes: Structure–Activity Correlations in β-Lactamase Model Systems

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Abstract

A series of highly preorganized pyrazolate-based dinuclear zinc complexes has been studied as functional synthetic analogues of metallo-β-lactamases, a class of bacterial enzymes that cause serious clinical problems because of their degradation of common β-lactam antibiotics. We have investigated the hydrolytic cleavage of penicillin G mediated by the different dinuclear zinc complexes, and have deduced structure–activity correlations. While cooperative effects of the adjacent metal ions might be operative, these are found to either enhance or diminish β-lactamase activity with respect to a single free zinc. Drastic differences in activity are ascribed to a lack of accessible binding sites after incorporation of the substrate within the bimetallic pocket of 2 and 4, whereas partial detachment of hemilabile ligand side arms in 1 and 3 opens up available coordination sites for nucleophile activation and/or for binding and polarisation of the β-lactam amide oxygen atom. This interpretation has been corroborated by NMR spectroscopic and mass spectrometric evidence as well as by X-ray crystallography of several adducts formed between the pyrazolate-based dinuclear zinc scaffolds and the small substrate analogue oxazetidinylacetate (oaa), 57. In all adducts, the carboxylate group of oaa is the primary anchoring site and is nested in a bridging position within the bimetallic pocket. However, zinc binding of the β-lactam amide oxygen atom has been confirmed crystallographically for the first time in 7, in which additional open-site coordination sites are available.

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