Cephalosporins aminolysis

Cephalosporins are mostly degraded via intramolecular aminolysis (see above, Fig. 5.8). However, high drug concentrations may also favor degradation via oligomer formation [119]. In the case of loracarbef (5.44, Fig. 5.16), which is not subject to intramolecular aminolysis, the formation of dimeric structures becomes predominant under moderately acidic conditions [120],... 

Efforts to produce more-stable compounds have yielded meropenem (5.47), which, although superior to other carbapenems, is less-stable than penicillins or cephalosporins. This lack of stability is confirmed by the formation of breakdown products identified as the dimers (5.48a and b) resulting from intermolecular aminolysis of the /Madam ring [100],... 

Penicillins and cephalosporins bind irreversibly to serum albumin. It has been shown that drug-protein conjugates result from the aminolysis of the /3-lactam bond by the e-amino group of lysine residues in the protein (Fig. 5.1, Pathway e). The bound penicilloyl group appears to be the major antigenic determinant of penicillin allergy [145-148],... 

For cephalosporins containing an amino group in the C7 side chain such as cephalexin, cephaloglycin, and cephradine, a polymerization can be imagined to occur by intermolecular aminolysis in the same way as the polymerization of am-picillin and other aminopenicillins. Such as reaction can, however, be expected to be much less effective for the cephalosporins since an autocatalyzed intramolecular aminolysis with the formation of piperazine-2,5-dione derivatives may occur to a much larger extent than an intermolecular aminolysis (Bundgaard 1976 c, d). 

Gutzwiller P (1974) Zum Problem der Kortikosteroid-Allergie. Dermatologica 148 253-256 Hamilton-Miller JMT, Newton GGF, Abraham EP (1970) Products of aminolysis and enzymic hydrolysis of the cephalosporins. Biochem J 116 371-384 Hertz CG (1973) The low incidence of side effects with cyclacillin. Arzneim Forsch [Suppl] 25 151-156... 

Bundgaard H (1974) Spectrophotometric determination of ampicillin sodium in the presence of its degradation and polymerization products. J Pharm Pharmacol 26 385 Bundgaard H (1975) Chemical studies related to cephalosporin allergy. I. Kinetics of aminolysis of cephalosporins and effect of C-3 substituents on beta-lactam reactivity. Arch Pharm 3 94... 

Fig. 5.14 Aminolysis of cephalosporins and decomposition products. With a good leaving group at C-3 (as in cefaclor and cephalothin), aminolysis in the presence of protein or polylysine leads to cleavage of the P-lactam ling via route 1. With a poor leaving group at C-3 (e.g.,...

In early studies on cephalosporin C in E. P. Abraham s laboratory in Oxford, acid hydrolysis yielded no penicillamine and alkali treatment led to fragmentation of the molecule. Aminolysis of cephalosporins in the presence of polylysine or protein gave results (including the appearance of... 

The work outlined above, and the interpretation of the chemical findings, indicates that as far as any resultant determinants are concerned, aminolysis results in structures in which only the R1 side chain, the attached amide, and remnants of the p-lactam ring remain from the original cephalosporin molecule. The resultant penaldate- and any penamaldate-like structures finked to carrier protein therefore represent hapten-carrier complexes that may interact with side chain (Rl)-specific IgE antibodies in allergic responses to therapeutic dosage of cephalosporin drugs. 

Fig. 5.15 Determination, prior to intended synthesis, of model structure with intact side chain remaining after aminolysis of cephalosporins. Adapted from Montanez MI et al. Synthetic Approach to Gain Insight into...

Hamilton-MiUer IMT, Newton GGF, Abraham EP. Products of aminolysis and enzymic hydrolysis of the cephalosporins. Biochem 1. 1970 116 371-84. 

There is spectroscopic and kinetic evidence that the aminolysis of cephalosporins proceeds by a stepwise mechanism (see Section 12), and, in general, it appears that 3 -eliminations are not concerted with P-lactam C—N bond cleavage when cephalosporins react with nucleophiles. 

The aminolysis of penicillins and cephalosporins is a stepwise process catalysed predominantly by bases which remove a proton from the attacking amine. The evidence for the reversible formation of a tetrahedral intermediate is kinetic and based on linear free-energy relationships (Page, 1984a). 

Similarly, the equilibrium constants for the formation of the tetrahedral intermediates, T, have been obtained. These vary substantially with the basicity of the amine from 4x 10 M" for 2-cyanoethylamine to 9x 10" M for propylamine. The Bronsted 3 uj-value for the equilibrium is 0.9. This provides experimental support for the Bronsted P-value of 1.0 that is often postulated for the formation of the tetrahedral intermediate from amines and carbonyl groups in which the amine nitrogen develops a unit positive charge, and presumably resembles the conjugate acid of the amine in structure and in its stability dependence upon substituents. Similar observations have been made in the aminolysis of cephalosporins (Page and Proctor, 1984), and these are discussed in Section 12. 

The aminolysis of cephalosporins follows a similar mechanism to that for penicillins (Proctor and Page, 1984). Although it has been suggested that the hydroxide-ion catalysed aminolysis involves proton transfer concerted with nucleophilic attack (Bundgaard, 1975), the Bronsted P -values of ca 1.0 are consistent with the stepwise mechanism. This is also supported by the non-linear dependence of the rate of aminolysis of cephalosporins upon hydroxide ion concentration (Proctor and Page, 1984) (see Section 12). 

There is a non-linear dependence of the rate of aminolysis of cephalosporins upon hydroxide ion concentration (Page and Proctor, 1984) which is consistent with a change in rate-limiting step and hence formation of an intermediate as described in Section 11. 

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... 

Data on the in vitro kinetics of hydrolysis and aminolysis of a large number of penicillins and cephalosporins have been reported (see, e.g.. 

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