Penicilloyl esters

The formation of penicilloyl esters can, for all penicillins, be greatly depressed or avoided by adjusting the pH of penicillin solutions containing the hydroxy com-... 

Larsen C, Bundgaard H (1978 b) Penicilloyl ester intermediates in glucose- and fructose-accelerated degradation of benzylpenicillin in aqueous solution. Arch Pharm Chem Sci 6 33-40... 

Zinc(II) and tris-buffers are effective catalysts for the aminolysis of benzylpenicillin. It is suggested that this is due to formation of a ternary complex in which the metal ion binds both penicillin and tris. Nucleophilic attack of the ionised hydroxyl on bound tris forms a penicilloyl ester which may then react with tris to form a penicilloyl amide (Schwartz, 1982 Tomida and Schwartz, 1983). A kinetically equivalent mechanism, however, would simply involve nucleophilic attack of tris on the zinc-penicillin complex. 

Several bacterial penicillin-binding proteins have been shown to be serine enzymes (Section 2). P-Lactamases are efficient and clinically important enzymes which play an important part in bacterial resistance to the normally lethal action of P-lactam antibiotics. A major class of P-lactamases are also serine enzymes that function by covalent catalysis with the intermediate formation of an acyl-enzyme (Knott-Hunziker et al., 1982 Cohen and Pratt, 1980 Fisher et al., 1980 Anderson and Pratt, 1983 Cartwright and Fink, 1982, Joris et al., 1984). The P-lactamase catalysed hydrolysis of a penicillin thus proceeds by formation of an acyl-enzyme which is an a-penicilloyl ester of a serine residue. The mechanism of reaction of penicillin with alcohols is therefore of obvious relevance, but in addition acyl transfer from nitrogen to oxygen nucleophiles is of current interest. 

Oxygen anions can catalyse the hydrolysis of penicillins by either acting as general bases or as nucleophiles. Several observations indicate that basic anions act as nucleophilic catalysts forming an intermediate penicilloyl ester [68] whereas weakly basic ones act as general base catalysts. 

Basic oxygen anions of pAT, > 9 act as nucleophilic catalysts for hydrolysis with the intermediate formation of a penicilloyl ester [68]. The reaction of... 

Fig. 14 Bronsted plot (solid line) for the second-order rate constants for the alcoholysis of benzylpenicillin against pfor the alcohol (-F). The broken line is for the second-order rate constant for the alkaline hydrolysis of a-penicilloyl esters [68]...

Penicilloyl esters of basic alcohols undergo reactions in addition to hydrolysis (Davis and Page, 1985) and these are discussed below. 

The pH-independent epimerisation of penicilloic acid at C(5) probably occurs by unimolecular ring opening of the thiazolidine to form the iminium ion tautomer of penamaldic acid [74]. There are two possible explanations for the base-catalysed reaction. Above pH 12 deprotonation of the iminium ion could become faster than ring closure, and the rate of epimerisation would increase because the steady state concentration of the ring-opened thiazolidine is increased. Alternatively, epimerisation could occur by the penamaldate mechanism followed by penicilloyl esters (Davis and Page, 1985). 

Under mildly alkaline conditions and in the presence of excess cyclo-heptaamylose the rate of degradation of penicillin is increased 2(U90-fold compared with the rate of alkaline hydrolysis (Tutt and Schwartz, 1971). Michaelis-Menten kinetics are observed which are indicative of complex formation. The apparent binding constant of 6-substituted penicillins varies little with the length of the alkyl side chain although it is increased about 10-fold for diphenylmethyl penicillin. The reaction is catalytic and hydrolysis proceeds by the formation of a penicilloyl- 3-cyclodextrin covalent intermediate, i.e. ester formation, by nucleophilic attack of a carbohydrate hydroxyl on the P-lactam. 

Around neutral pH a-penici)loyl esters [68] epimerise at C(5) faster than the ester function is hydrolysed (Davis and Page, 1985). If this occurs with penicilloyl enzymes from penicillins and the serine hydroxyl at the active site of the enzyme, the ring-opening of the thiazolidine generates electrophilic sites capable of irreversibly inactivating the enzyme. 

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... 

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