Penicillenic acids

Fig. 5.3 Degradation products ofbenzylpenicillin in solution A, penicilloic acid B, penicillenic acid C, penillic acid.

Fig. 5.7. The acid-catalyzed hydrolysis of penicillins involves first the formation of an acylium ion (5.22), which, by reacting with H20, yields penicil-loic acids 5.24 (Pathway b). The participation of a neighboring 6-acylamido group increases the rate of hydrolysis. During this intramolecular reaction (Pathway a), oxazolylthiazolidines (5.23) are formed and then give rise to the degradation products penicilloic acids 5.24, penicillenic acids 5.25,...

C. W. Parker, J. Shapiro, M. Kern, H. N. Eisen, Hypersensitivity to Penicillenic Acid Derivatives in Human Beings with Penicillin Allergy , J. Exp. Med. 1962, 115, 821-838. 

Pencillin is a reactive molecule both in vitro and in vivo, where it undergoes a slow transformation to a variety of products. The parent drug can react with protein, but some of the breakdown products (e.g., penicillenic acid) are more reactive than the parent drug and can... 

Penicillenic acid was conjugated to protein by an interesting procedure that included modification of the protein carrier. Penicillenic acid has a reactive sulfhydryl group capable of forming disulfide bonds with other... 

It is worth noting that the anhydro-a-phenoxyethylpenicillene (50), which can be obtained from (49) by oxidation with mercuric acetate, and which does not contain a /3-lactam ring, has significant activity (e.g. the MIC values toward S. aureus Smith and Kleb. pneumoniae are 0.5 and 3.13 Ug/ml, respectively). In contrast, the corresponding penicillenic acid is characterized by a complete lack of activity [61]. 

The imidazole-catalyzed isomerization of penicillin into penicillenic acids probably involves initial nucleophilic attack of imidazole on penicillin. Imidazole-catalyzed JV-acylimidazole hydrolysis was used by Charton in obtaining [Pg.292]

Dennen and Davis 35 reported from the Lilly Research Laboratories in 1961 on their kinetic study of the formation of penillic acid (V) and penicilloic acid (III) from phenoxymethyl and five other penicillins in acid solution. They made no mention of penicillenic acid (II) as an... 

Recently, Blinova and Khokhlov have studied the isomerization of phenoxymethyl penicillin into the corresponding penicillenic acid (II) 45 and phenoxymethyl penicillic acid penillic acid (V)J/ 46. However, an abstract to an earlier paper by Khokhlov and Blinova 47 reports phenoxymethyl penicillin does not isomerize to penillic acid. 

V, in aqueous and protein solutions, the ultraviolet absorption of penicillenic acid (compound II in Figure 3) is measured at 322 nm 87, 88,... 

Maleimides (Section 11.2.3.2.1.2) are particularly useful for the conjugation of thiol-containing haptens. Other approaches are based on the activation of the protein with bromoacetamide groups (Singh et al., 1978) or on the formation of disulfide bonds between the carrier and hapten in acetate buffer, pH 4.0, in the presence of hydrogen peroxide, as used for the conjugation of penicillenic acid (De Week and Eisen, 1960). 

Penicillins are also degraded by aqueous acids via initial reaction of the sidechain carbonyl group with the P-lactam. Penicillenic acids (33) are obtained when hydrolysis is carried out at pH 4, penillic acids (34) at pH 2. 

Sometimes, reactive intermediates are formed that are known or suspected to be toxic. For example, penicillins rearrange under acidic pH conditions to penicillenic acids, which are suspected to contribute to the allergenicity of penicillins (Scheme 3).4 Gosselin et al. 

Scheme 3. Representative example of the rearrangement of penicillins to their penicillenic acids under acidic pH conditions. (Reproduced from Ref. 4 with permission.)...

Rogers, M.E. Adlard, M.W. Saunders, G. Holt, G. High-performance liquid chromatographic determination of penicillins following derivatization to mercury-stabilized penicillenic acids. J.Liq. Chromatogr., 1983, 6, 2019-2031... 

However, at zero buffer concentration the maximum stability was shifted to a pH of 5.85. Ampicillin was stable in solutions at pH 3 - 9 when stored for 24 hours at 5°C and 25°C. Ampicillin was unstable in solutions at pH 10 when stored at above conditions. Bundgaard demonstrated a metastable intermediate in iso-meration of penicillin to penicillenic acid in aqueous solutions. The degradation of ampicillin trihydrate in solution is greatly influenced not only by pH, but also by the types of buffer salts used j. 2-Amino-2 (hydroxymethyl)-1,3-propanediol (Tris) buffer of pH 7 is highly deleterious to the stability of ampicillin, but not at pH 5.0. Citrate presents a converse pattern in that ampicillin is relatively stable at pH 7 but not so at pH 5. Phosphate is intermediate in action but tends to resemble the Tris pattern. Jacobson and Russo-Alesi prepared ampicillin trihydrate solutions at a concentration of 5 mg/ml by dissolving it in buffer solutions of pH 5.0 or pH 7.0 prepared from O.lM sodium acetate and acetic acid and in buffers of pH 8.0 or pH 8.8 prepared from O.lM 2-amino-2 (hydroxy methyl)- ,... 

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