Hydrolysis of cephalosporins

Another important site of structural variation in cephalosporins is C(3) (Table 5.4.J). Electron-withdrawing substituents at C(3) such as a Cl-atom or a MeO group increase base-catalyzed hydrolysis of cephalosporins by both resonance and inductive effects [92], For cephalosporins carrying 3-methylene-linked substituents with leaving group ability (e.g., acetate, thiol, or pyridine), it has been postulated that a concerted expulsion of the substituent facilitates the nucleophilic attack on the /3-lactam carbonyl group [104][105]. However, there are also arguments for a stepwise process in which the ex-... 

Fig. 5.20. Modes of coordination of transition metal ions with /3-lactam antibiotics. Complex A In penicillins, the metal ion coordinates with the carboxylate group and the /3-lactam N-atom. This complex stabilizes the tetrahedral intermediate and facilitates the attack of HO-ions from the bulk solution. Complex B In benzylpenicillin Cu11 binds to the deprotonated N-atom of the amide side chain. The hydrolysis involves an intramolecular attack by a Cu-coordinated HO- species on the carbonyl group. Complex C In cephalosporins, coordination of the metal ion is by the carbonyl O-atom and the carboxylate group. Because the transition state is less stabilized than in A, the acceleration factor of metal ions for the hydrolysis of cephalosporins is lower than for penicillins. Complex D /3-Lactams with a basic side chain bind the metal ion to the carbonyl and the amino group in their side chain. This binding mode does not stabilize the tetrahedral transition complex and, therefore, does not affect the rate of... 

Bontchev PR, Papazova P. Hydrolysis of cephalosporins in strongly acidic medium. Pharmazie 1978 33(6) 346-348. 

A Flinnen, J Nuesch. Enzymatic hydrolysis of cephalosporin C by an extracellular acetylhydrolase of Cephalosporium acremonium. Antimicrob Agents Chemother 9 824-830, 1976. 

Access to analogues with varied side-chains at the 7-position initially posed a problem. Unlike penicillins, it proved impossible to obtain cephalosporin analogues by fermentation. Similarly, it was not possible to obtain the 7-ACA (7-aminocephalosporinic acid) skeleton (Fig. 10.44) either by fermentation or by enzymic hydrolysis of cephalosporin C, thus preventing the semisynthetic approach analogous to the preparation of penicillins from 6-APA. 

Here as with the tetracyclines, the solution of difficult chemical problems was a prerequisite to successful new drug discovery. At first the counterpart of 6-aminopenicillanic acid could be made only in very low yields by chemical hydrolysis. A practical enzymatic hydrolysis of cephalosporin C to 7-aminocephalosporanic acid (7-ACA) was not found. R. B. Morin and co-workers provided the elegant solution (Figure 21) (101), which made the preparation of 7-ACA and semisynthetic cephalosporins possible on a practical scale. The impetus to persevere in this... 

Mechanism of Action. The drug is found to be resistant to certain -lactamases which are responsible for the hydrolysis of cephalosporins. It has been duly observed that cefoxitin helps to antagonize the action of cefamandole (see Section 3.2.1.2.1) against E. cloacae and also that of carbenicillin against P. aeruginosa. As the half-life is comparatively of shorter duration therefore, the drug must be administered 3 to 4 times per day. 

Antibacterial activities of novel active pharmaceutical ingredient ionic liquids based on ampicillin 31 have been evaluated (14MI4301). Structural and mechanistic insights into New Delhi metallo-P-lactamase catalyzed hydrolysis of cephalosporins have been reported (14JA14694). The hydrolysis of the antibiotic meropenem 32 by Escherichia coli cells carrying the gene for New Delhi metallo-P-lactamase, which confers antibiotic resistance, has been monitored by NMR spectroscopy in real time (14AGE2130). An... 

Glucose, sucrose, and polyhydric alcohols, glycerol, sorbitol, and mannitol, display nucleophilic reactivity with simple activated esters in aqueous solution buffered at neutral to alkaline pH. This nu-cleophylic reactivity is attributed to the anion resulting from ionization of a hydroxyl group. These polyhydric alcohols have been shown to be catalyt-ically active in the hydrolysis of cephalosporins in... 

Fig. 8 Hammett plot of the second-order rate constants for the hydroxide-ion catalysed hydrolysis of cephalosporins [11] against Charton s a, constant for the C(3) substituent.

The nmr chemical shifts of the C(8) P-lactam carbonyl carbon varies over only a very narrow range (Paschal et al., 1978 Dereppe et al., 1978 Schanck et al., 1979). However, there does appear to be a good linear relationship between the logarithms of the rate constants, Atqh, for the base catalysed hydrolysis of cephalosporins and the differences between the chemical shifts at C(3) and at C(4), A8(4 —3) (Nishikawa and Tori, 1981, 1984 Mondelli and Ventura 1977 Schanck et al., 1983). 

The acid hydrolysis of cephalosporins shows similar behaviour to that of the penicillins, but they are about lO -fold less reactive (Proctor et al., 1982). Electron-withdrawing substituents at C(7) in cephalosporins decrease the rate of acid hydrolysis and, as for penicillins, the Hammett p,-value is ca — 5. There is no evidence for neighbouring group participation by the 7-acylamido-group as postulated for the penicillins. There seems no obvious explanation of the difference in behaviour between the cephalosporins and penicillins. Either attack of water on the acylium ion (Scheme 5) could be... 

The P-lactamase catalysed hydrolysis of cephalosporins shows spectral changes in the ultraviolet which are consistent with the formation of [36] prior to expulsion of the leaving group at C(3 ) (Faraci and Pratt, 1984,1985 Agathocleous et al., 1984). 

Studies on the chemical aspects of penicillin allergy have shown that the penicilloyl determinant in penicillin allergy can be formed by the reaction of benzylpenicillenic acid with free functional groups in proteins, Benzylpenicillenic acid can react with SH groups of protein to form thio-esters similar to its reaction with amino groups to form amides a. Products obtained in aminolysis and enzymic hydrolysis of cephalosporins... 

We were unable to find the cephalosporin nucleus, 7-ACA, in fermentations of C. acremonium, but an attempt to obtain it by controlled acid hydrolysis of cephalosporin C was suggested by the relative acid stability of the 3-lactam ring of the latter. Experiments with Bronwen Loder (1959) showed that small amounts of 7-ACA could in fact be prepared in this way and that 7-ACA could be acylated to yield cephalosporins with higher activity than cephalosporin C. Whereas some of the procedures we had used in the isolation of penicillin N proved helpful in the isolation of 6-APA, the procedure introduced by the Beecham group for the phenylacetylation of 6-APA on paper facilitated our own work on 7-ACA. 

Hydrolysis of cephalosporin / -nitrobenzyl esters by microbial enzymes has been described. A convenient high-yield method for preparing benzhydryl esters of penicillins and cephalosporins has been described. Diphenyl-diazomethane is generated in situ in the presence of the antibiotic by oxidation with peroxyacetic acid of benzophenone hydrazone. Diazomethane has been found to add to 3-methyl-A -cephem sulphides, sulphoxides, and sulphones preferentially from the j3-side to give the respective pyrazolino-cephams (194 b). ... 

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