Penicillin modified penicillins

The IPNS enzyme has also been shown to recognize modified tripeptides. The synthesis of a range of tripeptides, other than aminoadipoyl cysteinyl valine (ACV) (Table 6), has given rise to a selection of modified penicillins using IPNS as a means of cyclizing the tripeptide (58). 

Table 6. Modified Penicillins Prepared Using IPNS...

Reslurrying can sometimes be advantageously employed for removal of impurities adsorbed on the surface. Anderson (2000) has given an example of the removal of excess p-nitrobenzyl bromide from a modified penicillin by reslurrying. 

The sulfonium ylide derived chemistry of penicillins continues to meet the interest of several research groups. It is well known that intermolecular carbenoid attack at the sulfur atom generates a sulfonium ylide which undergoes spontaneous opening of the thiazolidine ring to furnish a l,2-sm>-penicillin 326). Novel examples of this reaction type were found upon Rb2(0Ac)4-catalyzed decomposition of diazomalonic esters in the presence of various penicillins this transformation constituted the opening step of a synthetic sequence directed towards 2-alkoxycarbonyl-cephems 345 a) or modified penicillins 345 b). Similar to its reaction with 4-thio-2-azetidinone... 

The discovery of penicillin placed NPs back on the agenda of all the major pharma companies. Improved methods of production were developed and chemically modified penicillin analogues, with improved clinical value, were patented and widely adopted. Such was the optimism engendered by penicillin that it was rashly predicted that bacterial diseases would eventually be eradicated from the human population. Anyone with a reasonable knowledge of evolution and of NPs would have been surprised had that prediction come true. 

BuynakJD. The discovery and development of modified penicillin- and cephalosporin-derived beta-lactamase inhibitors. Curr Med Chem. 2004 11 1951-1964. 

CYE Wu, LC Blaszczak, MC Smith, PL Skatrud. Construction of a modified penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus and purification by immobilized metal affinity chromatography. J Bacteriol 176 1539-1541, 1994. 

Treatment of a penicillin sulfoxide with acetic anhydride affords the cephalosporin C ring system, although with different substituents. Medically useful drugs with a modified penicillin ring system will probably be found. 

The successes achieved in the past decade with chemically modified penicillins, tetracyclines, and lincomycin, undoubtedly influenced the judgment of the panel that preparation of structural analogs of useful antibiotics by chemical or other means should be ranked as one of the two most promising discovery approaches for the next decade. Before proceeding further with the evaluation made by the respondents of the five approaches (Table VII), some aspects of the history and nature of the structural modification approach are examined. 

Semisynthetic Penicillins. Just as the independent lines of inquiry of Dubos, Waksman, and the Oxford group converged to open the antibiotic era, the period of semisynthetic penicillin discoveries was initiated by a similar convergence. As an outgrowth of the early observation that the chemical nature of the penicillins produced by fermentation was influenced by the composition of the growth medium, the preparation of biosynthetic penicillins was accomplished by adding substituted phenyl-acetic acid derivatives (and related structures) to penicillin fermentations. By this method Behrens and co-workers at the Eli Lilly Co. had by 1948 prepared some 30 penicillins modified in the acyl moiety (64). 

The fledgling Beecham penicillin research team was stimulated by the advent of phenoxymethylpenicillin to seek additional superior penicillins modified in the acyl moiety (66). The general approach envisioned was the conversion of one penicillin bearing a reactive functionality to a variety of new modified penicillins specifically biosynthetic p-amino-benzylpenicillin was selected for modification via acylation of the amine function (Figure 15). 

Much of the interest in acylases originated from work with the penicillins. Structurally modified penicillins can by obtained by acylation of 6-aminopenicillamic acid. For example, the semisynthetic penicillins such as amoxicillin and ampicillin are obtained using enzymatic acylation. Acylases are used both to remove the phenyl-acetyl group from the major natural penicillin, penicillin G, and to introduce the modified acyl substituent. 

Pharmaceutical companies are involved in long, multi-step synthetic processes. A modest way in which they try to keep costs within bounds is by the use of standard intermediates that can be used for at number of products. For example, all the different chemically modified penicillins are based on 6-aminopenicillanic acid, which can consequently be manufactured on a much larger scale than any of the individual penicillins. Such intermediates are known as synthons. 

A particularly. successful and technically elegant biocataiytic process is the conversion of natural penicillin into a product that is necessary for the production of chemically modified penicillins. This product, known as 6-aminopenicillanic acid, is formed by splitting off the side chain of penicillin. 

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