Lactam substrate

SxxK (3-lactamases are uncoupled SxxK acyl transferases that work as (3-lactam antibiotic hydrolases. They represent a mechanism of defence of great efficiency. On good (3-lactam substrates, their catalytic centres can turn over 1000 times per second. 

Preparation of Chiral, Nonracemic Bicychc Lactam Substrates... 

For some bacteria (eg, Haemophilus species), the susceptibility patterns of strains are similar except for the production of 13 lactamase. In these cases, extensive susceptibility testing may not be required, and a direct test for 3 lactamase using a chromogenic 3-lactam substrate (nitrocephin disk) may be substituted. 

Mechanistic Aspects of /8-Lactamase Inhibition The clinically important /3-lactamases, e.g., the penases, TEM(lll). and cephases(I). are serine proteases that form an acyl enzyme intermediate with /1-lactam substrates and /i-lactam-derived /3-lactamase inhibitors. Mechanistic studies using several /3-lactamase inhibitors have been extensively reviewed and a general inhibition scheme is illustrated in Figure 1. 

Table 27 Rate Constants and Formation Constants for the Copper(II)-catalyzed Hydrolysis of /3-Lactam Substrates at...

The reduction of lactam substrates containing proximal exo double bonds may be achieved in high e.e. as demonstrated by the reduction of 3-alkylidene-2-piperidones (Scheme 19)119. Cyclic amino acids may be prepared by, for example, asymmetric hydrogenation of 3 to 4 in up to 79% e.e.120 and the reduction of 5 to 6 in 99% e.e.121. In the latter case a number of chiral diphosphines were screened, and the best results were obtained using BINAP as a ligand with rhodium metal. Several other diphosphines, notably DuPHOS and DIOP, also performed well. The research group which produced... 

Tpph,Me)Zn-OH] and [(TpCum,Me)Zn-OH] with the 7V-2,4-dinitrophenyl-appended 3-lactam substrate were monitored by H NMR under pseudo first-order conditions in CDC13. The second-order rate constants for these reactions were determined to be 0.57M-1 s-1 (Tpph,Me) and 0.13M 1s 1 (XpCum,Me) at 40oC The slower rate for the reaction involving [(TpCum,Me)Zn-OH] is consistent with the enhanced steric hindrance and hydrophobicity of the TpCum,Me ligand relative to Tpph,Me. 

Variable temperature kinetic studies for the hydrolysis of nitrocefin catalyzed by [Zn2L3(p-0H)(N03)2] in acetone DMSO yielded AH% = 88.4 + 5.3 kJlVT1 and A= —45.3 + 16.0 JM 1K 1. These values are similar to those found for nitrocefin hydrolysis catalyzed by [Zn2(BPAN)(ii-0H)( i-02PPh2)](C104)2 in 1 9 DMSO ac-etone (Akfi = 96.1 5.2kJM 1 and AS = —22.4+12 JM 1K 1) and are consistent with intramolecular attack by the bridging hydroxide on the coordinated P-lactam substrate in the rate-determining step.140... 

Generally, the initiators activate the inactive amide groups, causing them to react with other lactams through successive transamidations that result in formations of polyamides. Both acids and bases catalyze the transamidation reactions. The additions of electrophiles affect increases in the electrophilicity of the carbonyl caibon of the acylating lactam. The nucleophiles, on the other hand, increase the nucleophilic character of the lactam substrate (if they are bases). 

Metallo-P-lactamases [20] Zn(II)-Zn(II) Hydrolysis of P-lactam substrates (antibiotics) Study potential inhibitors to fight antibiotic resistance... 

Two Cd(II) complexes will be examined for their ability to hydrolyze OPs and p-lactam substrates. The mechanism of action will be probed using Cd-NMR, 0-labeling, solution IR and UV-Vis studies. The relevance of Cd(II) as biological metal and the observation of a blue intermediate in p-lactam hydrolysis will be discussed (Chap. 5). 

Another way to investigate the binding of lactam substrates to metal complexes... 

C02EtH3Ll and C02EtHL2 only differ in R" and allow comparison of the phosphoesterase-like activity in the presence and absence of alcohol nucleophiles. The model substrate BDNPP will be used. Also the ability of the complexes derived from these two ligands to hydrolyze substrates other than organophosphates will be investigated using the p-lactam substrates nitrocefin and penicillin G. 

In Fig. 6.30b the mass spectrum of [Co2(C02EtL2)(CH3COO)2] and penicillin G is shown. No hydrolysis of the penicillin was observed. This complex is however, also able to bind this lactam substrate as shown in the mass spectrum with the peak at m/z 1031.1 (calc, m/z 1030.3 (100 %), 1031.3 (52 %)). 

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