Hydrolysis of beta-lactam antibiotics catalyzed by dinuclear zinc(II) complexes: Functional mimics of metallo-beta-lactamases

Unspecified DOI: 10.1021/ja993704l Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: http://doi.org/10.5167/uzh-65632 Submitted Version Originally published at: Kaminskaia, N V; Spingler, Bernhard; Lippard, S J (2000). Hydrolysis of beta-lactam antibiotics catalyzed by dinuclear zinc(II) complexes: Functional mimics of metallo-beta-lactamases. Journal of the American Chemical Society, 122(27):6411-6422. DOI: 10.1021/ja993704l Dinuclear Models of a Metallo--lactamase – Hydrolysis of Lactam Antibiotics Catalyzed by Dinuclear Zinc(II) Complexes Natalia V. Kaminskaia, Bernhard Spingler, and Stephen J. Lippard* Contribution from the Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 Received Februarr 00, 2000 Abstract: Three stable dinuclear zinc(II) complexes, [Zn2L1(-NO3)(NO3)2] and [Zn2L1(OMe)(NO3)2], where L1 is 2,6-bis{[N-(2-dimethylaminoethyl)-N-methyl]-aminomethyl}-4methylphenolate, and [Zn2L2(NO3)3], where L2 is 2-{[N-(2-dimethylaminoethyl)-N-methyl]aminomethyl}-4-bromo-6-{[N’-2-( 2’-pyridyl)-ethyl]-aminomethyl}phenolate, were synthesized and characterized in the solid state and in aqueous solution. These complexes catalyze the hydrolysis of penicillin G and nitrocefin, serving as functional synthetic analogues of the metallo--lactamases, bacterial enzymes responsible for antibiotic resistance. The mechanism of the hydrolysis was studied in detail for the catalyst precursor [Zn2L1(NO3)(NO3)2], which converts into [Zn2L1(-OH)(NO3)n(sol)2-n](2-n)+ in aqueous solution. The complex [Zn2L1(-OH)(NO3)2] (n=2) was characterized in the solid state. Initial coordination of the substrate carboxylate group is followed by the rate-limiting nucleophilic attack of the bridging hydroxide at the -lactam carbonyl group. The product is formed upon fast protonation of the intermediate. Mononuclear complexes [Zn(cyclen)](OTf)2 and [Zn(bpta)](OTf)2 are as reactive in the -lactam hydrolysis as the dinuclear complexes. Consequently, the second zinc ion is not required for catalytic activity. Three stable dinuclear zinc(II) complexes, [Zn2L1(-NO3)(NO3)2] and [Zn2L1(OMe)(NO3)2], where L1 is 2,6-bis{[N-(2-dimethylaminoethyl)-N-methyl]-aminomethyl}-4methylphenolate, and [Zn2L2(NO3)3], where L2 is 2-{[N-(2-dimethylaminoethyl)-N-methyl]aminomethyl}-4-bromo-6-{[N’-2-( 2’-pyridyl)-ethyl]-aminomethyl}phenolate, were synthesized and characterized in the solid state and in aqueous solution. These complexes catalyze the hydrolysis of penicillin G and nitrocefin, serving as functional synthetic analogues of the metallo--lactamases, bacterial enzymes responsible for antibiotic resistance. The mechanism of the hydrolysis was studied in detail for the catalyst precursor [Zn2L1(NO3)(NO3)2], which converts into [Zn2L1(-OH)(NO3)n(sol)2-n](2-n)+ in aqueous solution. The complex [Zn2L1(-OH)(NO3)2] (n=2) was characterized in the solid state. Initial coordination of the substrate carboxylate group is followed by the rate-limiting nucleophilic attack of the bridging hydroxide at the -lactam carbonyl group. The product is formed upon fast protonation of the intermediate. Mononuclear complexes [Zn(cyclen)](OTf)2 and [Zn(bpta)](OTf)2 are as reactive in the -lactam hydrolysis as the dinuclear complexes. Consequently, the second zinc ion is not required for catalytic activity.