ISBN: 978-83-60043-10-3 - eurobic9

Eurobic9, 2-6 September, 2008, Wrocław, Poland
P205. New Binucleating Ligands for Modelling the Dizinc
Metallo-β-Lactamase Active Site
S. Wöckel a , B. Burger a , M. Jarenmark c , S. Dechert a , E. Nordlander c , F. Meyer a
a Institute for Inorganic Chemistry, University of Göttingen, Tammanstr. 4, D-37077, Göttingen, Germany
e-mail: Simone.Woeckel@chemie.uni-goettingen.de
c Center for Chemistry and Chemical Engineering, Lund University, Box 124, SE-22100, Lund, Sweden
β-lactamases are enzymes that mediate hydrolytic ring cleavage of β-lactams. They are thus responsible for the
increasing resistance towards widely used β-lactam antibiotics [1]. One group of these enzymes, so called
metallo-β-lactamases, contain one or two zinc atoms in their active site, which are ligated by amino acid residues
[2, 3]. The Lewis acidic character of zinc allows water to be deprotonated at physiological pH, generating
a nucleophilic hydroxide that is able to attack the β-lactam ring of the antibiotic substrate. Other roles of the
metal ions and details of the catalytic process are still controversial. In view of the importance of this class of
enzymes, further insight in the mechanism of β-lactam hydrolysis at dizinc sites is highly desirable.
We have developed a general class of ligands that can hold two metal ions in close proximity suitable for
cooperative reactivity. These tunable ligands are based on a central pyrazole bridge, substituted with chelating
side arms in 3- and 5- position of the heterocycle. Initial studies had provided some first insight into the binding
and cleavage of penicillin G at dizinc complexes of those ligands [4]. In order to more closely emulate
characteristic of the enzyme active site, we have now prepared several new ligand scaffolds that bear biomimetic
N- (imidazole or benzimidazole) or O- (carboxylate) side arm donor functions. Their synthesis and coordination
chemistry relevant to the metallo-β-lactamases will be presented.
References:
[1] I. Massova, S. Mobashery, Acc. Chem. Res. 1997, 30, 162-168.
[2] A. Badarau, M. I. Page, Biochemistry 2006, 45, 10654-10666.
[3] M. W. Crowder, J. Spencer, A. J. Vila, Acc. Chem. Res. 2006, 39, 721-728.
[4] B. Bauer-Siebenlist, S. Dechert, F. Meyer, Chem. Eur. J. 2005, 11, 5343-5352.
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