Cephalosporin from penicillins

The generation of cephalosporin from penicillin is dependent on the epimeriza-tion of the L-a-aminoadipyl side chain of isopenicillin N to the D-a-aminoadipyl side chain of penicillin N, since penicillin N but not isopenicillin N is the substrate for ring expansion enzymes [31], This reaction is catalyzed by IPNE ([32] Table 1) and is coded for by the cefD gene (Fig. 1 [5]). While the activity of the IPNE from C. acremonium has been studied in cell-free extracts, it has not been purified to date [2], Jensen et al. [33] described a partial purification and charac-... 

Without additional reagents Cephalosporin from penicillin ring skeleton WM.r. O... 

Methanesulfonic acid Cephalosporins from penicillin S-oxides O... 

The development of new antibiotics to combat resistance, and to provide easier oral administration and improved pharmacokinetics has been successful through synthetic modifications. This approach has been particularly rewarding in the area of P-lactams. The commercial importance of the P-lactams is evident from Table 3 which gives the market share of antibacterials. Fully 62% of the 1989 world antibacterial market belonged to the cephalosporin and penicillin P-lactams (20). 

From Four-membered Heterocycles, Cephalosporins and Penicillins... 

Different strains of micro-organisms are responsible for the production of either penicillins or cephalosporins. In penicillin-producing strains, an acyltransferase enzyme system is present which can remove the side chain from isopenirillin N to give 6-aminopenicillanic acid (6-APA), and which can subsequently acylate 6-APA to generate various penicillins, the most important ones being penicillin G and V(see section 6.3, Table 6.2). 

APA from penicillin G, 7-ACA from cephalosporin C, 7-ADCA from desaacetoxy cephalosporin G Biotransformation in steroids, e.g. cortexolone to hydrocortisone and prednisolone Food additives Lactic Acid (now a bulk chemical for making polylactate). Citric acid, L-Glutamate, L-Lysine, etc. Vitamines C, B2, B12 Acarbose (antidiabetic drug)... 

In addition to the amides described in ref. [72], further examples prepared by means of CDI from amino compounds of the cephalosporin or penicillin type, and various heterocyclic carboxylic acids, are reported in ref [86] and [87] and ref. [88] and [89], respectively. 

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. 

The common motif shared by non-heme iron oxygenases contains an active site, where two histidines and one carboxylate occupy one face of the Fe(ll) coordination sphere. These enzymes catalyze a variety of oxidative modification of natural products. For example, in the biosynthesis of clavulanic acid, clavaminic acid synthase demonstrates remarkable versatility by catalyzing hydroxylation, oxidative ring formation and desaturation in the presence of a-ketoglutarate (eq. 1 in Scheme 7.22) [80]. The same theme was seen in the biosynthesis of isopenicillin, the key precursor to penicillin G and cephalosporin, from a linear tripeptide proceeded from a NRPS, where non-heme iron oxygenases catalyze radical cyclization and ring expansion (eq. 2 in Scheme 7.22) [81, 82]. 

Hypersensitivity reactions Reactions range from mild to life-threatening. Before therapy is instituted, inquire about previous hypersensitivity reactions to cephalosporins and penicillins. 

Hameed TK, Robinson JL. Review of the use of cephalosporins in children with anaphylactic reactions from penicillins. Can J Infect Dis 2002 13(4) 253-8. 

Reactive extraction studied for cephalosporins and penicillins using different carriers and solvents can now be applied in LM for their separation from practical point of view [50-52]. In a typical membrane formulation of an oil phase... 

Early examples of successful, highly diastereoselective alkylations of bicyclic /1-lactams include reactions of the enolates from penicillin and cephalosporin derivatives (e.g., 1 and 4). These enolates have also been used in aldol-type additions, acylations and in the preparation of hetero-substituted penicillins and cephalosporins1. 

At present all of the cephalosporins ate manufactured from one of four fi-lactams, cephalosporin C, penicillin V. penicillin G, and cephamycin C, which are all produced in commercial quantities by fermenialion. The... 

Thiazoline-azetidinones 1 derived from penicillins G and V4) are potential intermediates for penicillin-cephalosporin conversion, where the oxidative functionalization of the methyl group of the 3-methyl-3-butenoate moiety is an essential step. The direct chlorination of 1 with chlorine (25 °C, 3 days) or /-butyl hypochlorite (—60% yields) gives the corresponding chlorinated compounds 2, bearing benzyl, phenyl, p-tolyl, and phenoxymethyl groups as the R3 substituents 5). 

About one-third of the commercial cephalosporins are derived from 7-ADCA. Due to the lower cost of penicillin, 7-ADCA is usually produced from penicillin G by ring expansion of a penicillin sulfoxide ester to yield a cephalosporin ester. The removal of the ester group is followed by cleavage of the phenylacetyl side chain to give 7-ADCA. Two-thirds of the commercial cephalosporins are derived from 7-ACA, that is produced from CPC by either chemical or enzymatic deacylation. 

This section aims to complete the picture on the studies summarized in CHEC-II(1996) on the synthesis of classical cephalosporins, describing the main cephalosporin methodologies developed during the last decade. In CHEC-II(1996), an approach was presented for the formation of the cephalosporin framework bearing various heteroatom and carbon substituents at the C-3 position, which relies on a sequential addition/cyclization of allenoate 70, derived from penicillin G. 

To date, the number of penicillin and cephalosporin-based molecules produced by semi- and total synthesis is well in excess of 20000. Most started with modification of the fermentation product, 6-amino-penicillanic acid 20 or the corresponding cephalosporin, 7-amino-cephalosporanic acid 21, both of which can be produced by simple chemical or biochemical deacylation from penicillin or cephalosporin C. The number above is only approximate as a significant proportion of structures from industry were never formally published, or were only mentioned in the patent literature—particularly if they had marginal or no significant activity levels over those which had been reported previously. 

Penicillin G as well as approx. 4 kt a-1 of penicillin V are enzymatically hydrolyzed into the -lactam nucleus 6-aminopenicillanic acid (6-APA), which is the building block for the semisynthetic penicillin antibiotics ampicillin and amoxycillin [121] (see Fig. 8.23). Part of the penicillin G is converted into 7-aminodesa-cetoxycephalosporanic acid (7-ADCA, 3 kt a-1), which is the intermediate for the semisynthetic cephalosporins cephalexin and cefadroxil [122]. 7-ADCA has traditionally been produced from penicillin G via a chemical ring expansion but an all-bio process has recently been started up by DSM. 

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