Penicillins, semi-synthetic

Many semi-synthetic penicillins are made from 6-aminopenicillanic acid (6-APA, R = NH2>. 

Figure 6.14 Enzymatic side chain cleavage of penicillins. 6-Aminopenicillanic acid, a valuable intermediate for the production of various semi-synthetic penicillins, can be obtained through enzyme-mediated hydrolysis of the phenylacety group of penicillin G or the phenoxyacetyl group of penicillin V. The active site of the enzyme recognises the aromatic side chain and the amide linkage, rather than the penidllin nucleus. Chemical entitles other than penicillins are therefore often good substrates, as long as they contain the aromatic acetamide moiety.

Before we leave our discussion of preparing 6-aminopenicillanic acid for use as a starting material in the manufacture of semi-synthetic penicillins, we should point out that similar processes are used in the manufacture of semi-synthetic cephalosporins. Here tire key intermediate is 7-aminodeacetoxycephalosporanic add (7-ADCA). We have drawn outline schemes comparing the production of semi-synthetic penicillins and cephalosporins in Figure 6.15. You will see that the two schemes are very similar. 

Figure 6.15 Production of semi-synthetic penicillins (left) and cephalosporins (right), from enzymatically obtained intermediates 6-APA and 7-ADCA respectively.

In section 6.6.1, we described how enzymatic methods have come to dominate the production of the important intermediates used in the manufacture of semi-synthetic -lactams. In principle, the hydrolytic penicillin acylases may be used in the reverse direction to add acyl groups to 6-APA. For example, a two-step enzymatic process has been described for the preparation of ampiciilin (D-(-)-a-aminobenzylpenidllin structure shown in Figure 6.17). 

Also illustrated in Figure 6.17 there is another important antibiotic, amoxicillin. Both amoxicillin and ampiciilin can be made enzymatically or chemically. Although enzymes are available that can be applied very well for the conversion of 6-APA into a variety of semi-synthetic penicillins, economic reasons are still impeding large scale applications. 

Rasor and Tischer (1998) have brought out the advantages of enzyme immobilization. Examples of penicillin-G to 6-APA, hydrolysis of cephalospwrin C into 7-ACA, hydrolysis of isosorbide diacetate and hydrolysis of 5-(4-hydroxy phenyl) hydantom are cited. De Vroom (1998) has reported covalent attachment of penicillin acylase (EC 3.51.11) from E.Coli in a gelatine-based carrier to give a water insoluble catalyst assemblase which can be recycled many times, and is suitable for the production of semi-synthetic antibiotics in an aqueous environment. The enzyme can be applied both in a hydrolytic fashion and a synthetic fashion. 6-APA was produced from penicillin-G similarly, 7-ADCA was produced from desa acetoxycephalosporin G, a ring expansion product of penicillin G. 

The p-lactams, mainly penicillins and cephalosporins, are by production volume the most important class of antibiotics worldwide, enjoying wide applicability towards a range of infectious bacteria. Most of the key molecules are semi-synthetic products produced by chemical modification of fermentation products. Production of these molecules has contributed significantly to the development of large-scale microbial fermentation technology, and also of large-scale biocatalytic processing. 

Semi-synthetic penicillins are accessed from 6-aminopenicillanic acid, (6-APA), derived from fermented penicillin G. Starting materials for semi-synthetic cephalosporins are either 7-aminodesacetoxycephalosporanic acid (7-ADCA), which is also derived from penicillin G or 7-aminocephalosporanic acid (7-ACA), derived from fermented cephalosporin C (Scheme 1.10). These three key building blocks are produced in thousands of tonnes annually worldwide. The relatively labile nature of these molecules has encouraged the development of mild biocatalytic methods for selective hydrolysis and attachment of side chains. 

After removal of the carboxylic acid portion of the original amide, a new amide linkage is generated, e.g. by reaction with a suitable acyl chloride. One of the first commercial semi-synthetic penicillins, methicillin, was produced as shown. Other agents, e.g. ampicillin, may be produced by similar means, though sensitive functional groups in the new side-chain will need suitable protection. 

Penicillins refer to a family of both natural and semi-synthetic antibiotics. Although all exhibit a 6-aminopenicillanic acid core ring structure (Figure 1.15), they differ in the structure of their side-chains. Naturally produced penicillins include penicillins G and V. Semi-synthetic penicillins can be manufactured by enzymatic removal of a natural penicillin side-chain (using... 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

Tetracyclines are a family of antibiotics which display a characteristic 4-fused-core ring structure (Figure 1.16). They exhibit broad antimicrobial activity and induce their effect by inhibiting protein synthesis in sensitive microorganisms. Chlortetracycline was the first member of this family to be discovered (in 1948). Penicillin G and streptomycin were the only antibiotics in use at that time, and chlortetracycline was the first antibiotic employed therapeutically that retained its antimicrobial properties upon oral administration. Since then, a number of additional tetracyclines have been discovered (all produced by various strains of Streptomyces), and a variety of semi-synthetic derivatives have also been prepared (Table 1.18). 

D-p-Hydroxyphenylglycine is an important component of certain semi-synthetic antibiotics such as the semi-synthetic cephalosporins cefadroxil and cefatrizine and the semi-synthetic penicillin amoxicillin, with a combined world market in excess of 3 x 10 /a. Synthesis was possible from DL-5-monosubstituted hydantoins (cyclic ureides of amino acids) provided that a selective D-hydantoinase could be found, which would be competitive with chemical methods. 

Some typical commercial biotechnology products are citric acid, semi-synthetic penicillins and cephalosporins, and vitamin B12. World production volumes and bulk prices show a considerable range of values. Prices tend to be inversely proportional to the amount of product sold, that is, the scale of production, and to the concentration at which it can be produced in the bioreactor. The importance of the concentration at which each product is produced in determining the cost of purification and isolation, and thus the... 

In the drug discovery stage, suitable sources are explored. Sources of drug molecules can be natural, e.g. narcotic analgesic, morphine, from Papaver somnifemm (Poppy plant), synthetic, e.g. a popular analgesic and antipyretic, paracetamol, or semi-synthetic, e.g. semi-synthetic penicillins. 

Penicillin C (or V) Amidase (PGA, PVA) /1-Lactam Precursors, Semi-synthetic /1-Lactams... 

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