Theoretical Studies on the Ring Opening of β-lactams: Processes in Solution and in Enzymatic Media

Author(s): R. Lopez, M. I. Menendez, N. Diaz, D. Suarez, P. Campomanes, D. Ardura, T. L. Sordo.

Journal Name: Current Organic Chemistry

Volume 10 , Issue 7 , 2006

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Abstract:

Herein we present an overview of the theoretical studies on the cleavage of the β-lactam C-N bond in aqueous solution and in enzymatic media. We discuss first the alkaline hydrolysis of β-lactams that has been investigated thoroughly by means of semiempirical, ab initio, and density functional calculations, while solvent effects have been typically included using a discrete and/or continuum representation of solvent. These computational studies investigate the origin of the energy barrier, the structure and stability of tetrahedral intermediates, substituent effects, catalysis by transition metals such as Zn(II) and Cu(II), etc. Other recent articles have been devoted to the analysis of the acidic and neutral hydrolysis/alcoholysis of β-lactams as well as their ozonolysis. We also review a series of theoretical studies that describe the ammonolysis/aminolysis of monocyclic and bicyclic β-lactams using density functional calculations combined with a solvent continuum model. The aminolysis reaction between the lysine 199 residue of Human Serum Albumin and benzylpenicillin is also revised. The second part of this review concentrates on the β-lactam ring opening catalyzed by the "penicillin recognizing proteins" family of bacterial enzymes, which includes both serine-proteases and zinc-proteases. For the serine proteases ( β-lactamases and penicillin binding proteins), quantum chemical optimizations on cluster models of their active sites and hybrid quantum chemical and molecular mechanical calculations on the whole enzymes, have been applied to examine several competing mechanisms that differ in the identity of the required base to activate the nucleophilic serine. For the zinc- β-lactamases, the gross of computational work has been aimed at examining the coordination chemistry of the catalytic metal centers, and only a few mechanistic studies have been reported to date.

Keywords: Alcoholysis, acidic hydrolysis, 2-Azetidinone, Zwitterionic Intermediates, Ozonolysis, Penicillin binding proteins

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Article Details

VOLUME: 10
ISSUE: 7
Year: 2006
Page: [805 - 821]
Pages: 17
DOI: 10.2174/138527206776818883
Price: $58

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