Penicillins aminolysis

Tsuji A, Yamana T, Miyamoto E, Kiya E (1975) Chemical reactions involved in penicillin allergy kinetics and mechanism of penicillin aminolysis. J Pharm Pharmacol 27 580 Tuft L, Gregory DC, Gregory I (1955) Evaluation of skin testing methods employed in the diagnosis of penicillin allergy. Am J Med Sci 230 370 Utley PM, Lucas JB, Billings TE (1966) Acute psychotic reactions to aqueous procaine penicillin. South Med J 59 1271... 

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],... 

Kinetic studies of the unnatural 6-a -epimer of ampicillin, fi-ept-ampicillin (154), have revealed an intramolecular process not undergone by ampicillin (or other natural /3-substituted penicillins) At pH 6-9, intramolecular attack of the jS-lactam carbonyl group by the side-chain amino group of (154) yields a stable piperazine-2,5-dione derivative (155). Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the a-face of the -lactam ring with an activation energy of 14.4kcalmor In other respects, the hydrolysis of the b-a-epimer is unexceptional. 

Theoretical studies were reported of the thiolysis by 2-mercaptoethanol and 2-mer-captoethylamine of simple models of the bicyclic ring systems of penicillin and cephalosporin88 and of the alkaline hydrolysis of sanfetrinem (93)89 The major determinant in allergies induced by penicillins is the penicilloyl group bound to the amino group of the Lys residues present in the carrier protein. Now a study is reported of the polyelectrolyte polyethylenimine (94) as a model of the carrier protein and its catalysis of the aminolysis of benzylpenicillin.90... 

An example of a proton-transfer reaction occurring by the stepwise trapping mechanism (Ch. 7, Section 2.1) is the general base-catalysed aminolysis of benzyl-penicillin. Amines react with penicillin to form an unstable tetrahedral intermediate which may be trapped by a diffusion-controlled encounter with a strong base as shown in Eqn. 8. Diamines also undergo this reaction but at a much faster rate than monoamines of the same basicity which is attributed to intramolecular general base catalysis i.e. the second amino group acts as a proton acceptor (V). However, the effect of intramolecularity itself is small and the effective concentration (Ch. 1)... 

Intermolecular general base catalysis 234 Intramolecular general base catalysis 241 Intramolecular general acid catalysis and the direction of nucleophilic attack 243 Uncatalysed aminolysis 244 Metal-ion catalysed aminolysis 246 Imidazole catalysed isomerisation of penicillins 248 Intramolecular aminolysis 249... 

There have been several studies on the self aminolysis of penicillins containing amino groups which leads to dimerisation and polymerisation products (Bundgaard, 1977a,b Larsen and Bundgaard, 1977, 1978a,b). The... 

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). 

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