Benzylpenicillin substances

Semisynthetic. In 1959, scientists at Beecham Researeh Laboratories sueceeded in isolating the penicillin nucleus, 6-aminopenicillanie aeid (6-APA Fig. 5.1 A R represents H). During the commercial production of benzylpenicillin, phenylacetic (phenylethanoic) acid (C6H5.CH2.COOH) is added to the medium in whieh the Penicillium mould is growing (see Chapter 7). This substance is a precursor of the side... 

In usual practice, however, benzylpenicillin sodium is standardised against a chemical reference substance of pre-determined potency. 

About a decade later, a group of researchers at Oxford University isolated a crude substance made up of a few low-molecular substances, which were penicillins (F, G, K, O, V, X). Penicillin G (benzylpenicillin), the most active of these, was suggested for clinical trials in 1941. 

Penicillins (A). The parent substance of this group is penicillin G (benzylpenicillin). It is... 

Of simpler substances can be mentioned phenylacetic acid as a constituent of benzylpenicillin 0-methyltyrosine in, e.g., the antibiotic puromy-... 

During the same period, Sheehan was working toward a total synthesis of penicillins. In 1958, he announced the synthesis of 6-amino-penicillanic acid (6-APA) and its utility for the preparation of new penicillins by acylation (67, 68). (Almost 10 years earlier, this substance had been postulated to be an intermediate in the biosynthesis of penicillins (69, 70). Prior Japanese literature also contained clear suggestions that it had been formed by enzymatic hydrolysis of benzylpenicillin (71) and in fermentations carried out in the absence of side chain precursors... 

Figure 80. Effect of phosphate concentration on hydrolysis rate of representative drug substances for which phosphate buffer catalysis is observed, o, Benzylpenicillin, 60°C, pH 7.05 A, cefadroxil, 35°C, pH 7.20 , carbenicillin, 35°C, pH 7.48. (Reproduced from Refs. 71, 381, and 382 with permission.)...

Studies on the inactivation of benzylpenicillin have shown that this substance has a strong preference for acylating j8-aminomercaptans, much less affinity for other amines, and none for other mercaptans. The product [e.g. 13.6) from j8-mercaptoethylamine] is acylated on the amino-group. The function of the mercapto-groups seems to be to form a hydrogen bond with the oxygen atom of the lactam and hence increase the polarization of the C=0 bond in the penicillin. 

In 1967 Batchelor et al. (1967) described the formation of a higher molecular weight substance in concentrated aqueous solutions of benzylpenicillin when they were left to stand for a short time at room temperature. The substance was shown... 

Smith et al. (1971) have determined the amount of polymers (i.e., substances which elute in the higher molecular weight range on Sephadex G-25 gel chromatography) formed in aqueous solutions (25% W/V) of a number of penicillins stored at room temperature. The solutions were not buffered. The results obtained are shown in Table 1. In another study, these investigators (Dewdney et al. 1971) have demonstrated that the amounts of polymers formed in a 25% W/V solution of benzylpenicillin sodium are greatly reduced if a phosphate buffer (pH 7.5) is included in the solution. A similar observation has also been made by de Weck et al. (1968) in the case of a 10% W/V penicillin solution. This reduction in polymerization... 

Davies RJ, Hendrick DJ, Pepys J (1974) Asthma due to inhaled chemical agents Ampicillin, benzylpenicillin, 6-amino penicillanic acid related substances. Clin Allergy 4 227... 

IV. Antibiotic Dusts Ampicillin, Benzylpenicillin, 6-AminopeniciIlanic Acid and Related Substances... 

Cephalosporin C, which contains a dihydrothiazine-j8-lactam ring system, shows at least 10% of the activity of cephalosporin N against Staph, aureus and induces the formation of the enzyme penicillinase by Staph, aureus and Bacillus cereus. This may be attributed to the fact that the stereochemistry of a major part of the cephalosporin C nucleus is similar to that of 6-aminopenicillanic acid. The precise factors which determine the ability of a substance to act as an inducer of penicillinase are clearly different from those which make the substance a good substrate of the enzyme. The /9-lactam ring in cephalosporin C is insensitive to penicillinase. However, the affinity of a substance for a penicillinase varies with the source of the enzyme. Cephalosporin C acts as a competitive inhibitor of the action of penicillinase from Bacillus cereus, but not from Staph, aureus, on benzylpenicillin. In contrast, the V-phenylacetyl derivative of 7-aminocephalosporanic acid is a powerful inhibitor of the staphylococcal enzyme12... 

A substance which resembled 6-aminopenicillanic acid was detected in small amount among the products formed by a Cephalosporium sp. when the latter was grown in certain media (Cole and Rolinson, I96I). However, no 7-amino-cephalosporanic acid has yet been found among the extracellular, or intracellular, products of this organism and if it is an intermediate in the biosynthesis of cephalosporin C it attains only very low stationary concentrations. It is of interest, in this connection, that penicillin amidases, which catalyse the hydrolytic removal of the phenylacetyl sidechains of benzylpenicillin and 7-phenylacetamidocephalo-... 

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