The copper(II) promoted hydrolysis of benzylpenicillin. Evidence for the participation of a Cu–OH species in the hydrolysis of the β-lactam ring

Metallo‐β‐lactamases and Their Biomimetic Complexes

“…[35,92,93,95,99] the reaction of a metal ion complex of the β-lactam itself. [106,107] The role of the metal-ionbound hydroxide moiety as the active nucleophile was established in these studies with an acceleration rate of about 10 7 reported in the case of the copper(II) complex of penicillin G. [104][105][106] In addition, the coordination of the metal ion through the β-lactam nitrogen atom and the carboxylate group was demonstrated. [106,107] The role of the metal-ionbound hydroxide moiety as the active nucleophile was established in these studies with an acceleration rate of about 10 7 reported in the case of the copper(II) complex of penicillin G. [104][105][106] In addition, the coordination of the metal ion through the β-lactam nitrogen atom and the carboxylate group was demonstrated.…”

“…Dinuclear MβL models with varying bridging and coordinating moieties. These studies focused on the metal ion and the β-lactam without full knowledge of the active sites of the metalloenzymes themselves, in particular on the copper(II) and manganese(II) complexes of, for example, penicillin G, [103][104][105] as well as copper(II), zinc(II), nickel(II), and cobalt(II) complexes of penicillin and cephalosporin derivatives [104] and amide analogues. These studies focused on the metal ion and the β-lactam without full knowledge of the active sites of the metalloenzymes themselves, in particular on the copper(II) and manganese(II) complexes of, for example, penicillin G, [103][104][105] as well as copper(II), zinc(II), nickel(II), and cobalt(II) complexes of penicillin and cephalosporin derivatives [104] and amide analogues.…”

“…These studies focused on the metal ion and the β-lactam without full knowledge of the active sites of the metalloenzymes themselves, in particular on the copper(II) and manganese(II) complexes of, for example, penicillin G, [103][104][105] as well as copper(II), zinc(II), nickel(II), and cobalt(II) complexes of penicillin and cephalosporin derivatives [104] and amide analogues. [104,105,108] Studies of the methanolysis of N-aryl-β-lactams and nitrocefin with zinc(II) and lanthanum(III) have also been reported. [104,105,108] Studies of the methanolysis of N-aryl-β-lactams and nitrocefin with zinc(II) and lanthanum(III) have also been reported.…”

A Theoretical Analysis of the Coordination Modes of CuIIwith Penicillins: Activation of the β‐Lactam CN Bond

“…Many experimental works have reported the formation of Cu II –penicillin complexes and proposed different modes of complexation 5–7. 9, 10, 23–26 It has been suggested that copper coordinates to the nitrogen atom of the 6‐amido side chain (see Scheme for atom numbering) and to the oxygen atom of the β‐lactam carbonyl group (see A in Scheme ) 5. Nevertheless, NMR studies23 and the fact that replacement of the 6‐amido side chain by the more basic amino group, or by hydrogen, has little effect on the binding constant of the Cu II – penicillin complex or on the enhancement of the hydrolysis rate by the metal ion, seem to indicate that this mode of binding does not occur 7.…”

“…7, 9 Recently, experimental evidence for this type of complexation was found for dicloxacillin (see Scheme ), with which Cu II exhibits square‐planar coordination 26. In contrast, no evidence was found for this kind of coordination in a potentiometric study, which concluded that copper bonds to the nitrogen atom of the 6‐amido side chain of penicillin and to the β‐lactam nitrogen atom (see C in Scheme ) 10. In the case of ampicillin (see Scheme ) UV, Vis, and IR spectroscopic data show that Cu II coordinates only to the carboxylate group (see D in Scheme ) 24.…”