Penicillin nucleus

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

Penam P-Lactamase Inhibitors. Penam is the trivial name given derivatives of the penicillin nucleus (31) the chemical name of which is 4-thia-l-a2abicyclo[3.2.0]heptane. Table 6 gives activity data for a diverse group of penams. The report that 6-P-bromopeniciU.anic acid [26631-90-3] [2(3)-(2a,5a,6P)]-6-bromo-3,3-dimethyl-7-oxo-4-thia-l-a2abicyclo[3.2.0]heptane-2-carboxyhc acid, (31, R = Br, R =H, R" = R " = CH3) a potent... 

Chemical Modification. Chemical modification of most positions in the penicillin nucleus have been carried out and these are summarized in Table 4. Apart from acylation of 6-APA, few of these modifications have proven profitable in terms of improving the biological properties of the derived penicillins. However, one of the modifications that has led to beneficial properties is substitution at the 6a-position. 

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... 

There has also been extensive activity towards the replacement of the entire chemical route to 7-ADCA (Scheme 1.14) with a biocatalytic one. This is somewhat more complex than the above example, as the penicillin fermentation product requires ring expansion as well as side-chain hydrolysis in order to arrive at the desired nucleus. The penicillin nucleus can be converted to the cephalosporin nucleus using expandase enzymes, a process that occurs naturally during the biosynthesis of cephalosporin C by Acremonium chryso-genum and cephamycin C by Streptomyces clavuligems from isopenicUhn N (6-APA containing a 6-L-a-aminoadipoyl side chain). ... 

An extremely important progress in the development of penicillins took place in 1959, when the penicillin nucleus, 6-aminopenicillanic acid (6-APA), was removed from the side chain and isolated from a culture of Penicillium chrysogenum. 

The cephalosporin nucleus is synthesized with a beta-lactam ring attached to a six-membered dihydrothiazine ring. Unlike the penicillin nucleus, the cephalosporin nucleus is much more resistant to beta-lactamase. Moreover, it has large areas for possible modifications. Modifications Rj in the acyl side chain alter the antibacterial activity, while modifications of R2 are associated with changes in the pharmacokinetics and metabolic parameters of the drug. 

Amoxicillin 6-[D-)-a-Amino-p- hydroxyphenylacetamido] penicillanic acidc Aromatic alkylation, amination, imine formation, amidation (sidechain), fermentation, and deamidation (penicillin nucleus)... 

It is derived from penicillin nucleus 6-aminopenicillanic acid. It has broad spectrum of activity against both gram positive and negative organisms. It is more potent than carbenicillin against Pseudomonas. 

Semi-Synthetic Antibiotics. In 1959, Batchelor and coworkers in the Beecham Research Laboratories in England discovered that the penicillin nucleus, 6-aminopenicil-lanic acid (6-APA), accumulated during fermentation when side chain precursors were omitted. This 6-APA could be used for the chemical synthesis of entirely new types of penicillin by coupling with new side chains. Shortly thereafter, several sources of penicillin amidase were found that would cleave the phenylacetyl side chain from penicillin G, thus producing a more economical source of 6-APA. A vast number of synthetic penicillins have been generated, and a few have achieved clinical importance. Several objectives were sought ... 

In 1948, the ring-expanded version of penicillin, cephalosporin C 22, was reported from Cephalosporium sp. by Brotzu its structure was determined in 1961 by the Oxford group.42,43 As with the penicillin nucleus, this ring-expanded molecule, 7-aminocephalosporanic acid 21, also served as the building block for many thousands of cephalosporins with the first orally active molecule, cephalexin 23 being introduced in 1970. Since that time, a multitude of cephalosporins have been synthesised with the aim of producing molecules that are more resistant to (3-lactamases. 

The chemical process for 7-ADCA dates back to the early days of cephalosporin chemistry [123] and involves the sequential sulfoxidation, esterification and dehydratation/expansion of the penicillin nucleus. The yields were low, initially, but improved as the result of a considerable research effort [124]. An optimized... 

The basic penicillin nucleus has been and continues to be chemically modified to produce penicillins with imique advantages. Based on their spectra of antibacterial activity and their clinical applications, the penicillins can be divided into four categories (Table 11-3). 

Benzylpenicillin (1942) is produced by growing one of the penicillium moulds in deep tanks. In 1957 the penicillin nucleus (6-amino-penicillanic acid) was synthesised and it became possible to add various side-chains and so to make semisynthetic penicillins with different properties. It is important to recognise that not all penicillins have the same antibacterial spectrum and that it is necessary to choose between a number of penicillins just as it is between antimicrobials of different structural groups, as is shown below. 

By 1959, Rolinson and coworkers completed the isolation of the penicillin nucleus, 6-aminopenicil-lanic acid, (Figure 1) in quantity. At about the same time the p-lactam-dihydrothiazine structure for the cephalosporin C was proposed [2] and confirmed subsequently by X-ray crystallographic analysis. In 1962, Morin and coworkers established a chemical method for the production of 7-aminocephalosporanic acid (Figure 1) from cephalosporin C in quantity. These developments opened the way to the preparation of... 

Diazoalkanes, e.g. ethyl diazoacetate, may also be employed as carbene precursors the novel conversion of the cephalosporin (10) to the penicillin nucleus (11) (Scheme 5) illustrates the potential of this method. 

The classical iodometric assay of penicillins [S9] is applicable to amoxicillin and was the required procedure in the US Pharmacopoeia [60] prior to introduction of HPLC in 1991. This method is based on the fact that the intact penicillin nucleus does not react with iodine, but reaction does occur after hydrolysis to the penicilloic acid. Any penicilloic acid or other iodine reactive compounds present in the sample as impurities are corrected for by a blank titration of unhydrolysed penicillin. A slight variation of the standard procedure is required for amoxicillin and ampicillin in which a small amount of HC1 is added to the blank to release bound iodine which would otherwise cause false results [61], The reaction between iodine and penicilloic acid does not have an exact stoicheiometry and results are calculated relative to the purity of a reference standard which is assayed simultaneously with the sample. 

Fortunately, it is found that acyloxymethyl esters are susceptible to non-specific esterases. These esters contain a second ester group further away from the penicillin nucleus which is more exposed to attack. The products which are formed from hydrolysis are inherently unstable and decompose spontaneously to reveal the free carboxylic acid (Fig. 10.38). 

The synthesis of 3-methylated cephalosporins from cephalosporins is very difficult and it is easier to start from the penicillin nucleus as shown in Fig. 10.48. The... 

After World War 11, Beecham s Group was the oldest established drug company in Britain, but the least successful of that nation s three entrants into the postwar therapeutic revolution. Beecham s, ranked fourteenth in Table 91, had by 1967 jumped to second place. Nevertheless, these sales came primarily from OTC drugs and related consumer products. It opened its first research unit only in 1947. Its first new success debuted in 1957 with the introduction of a second-generation formed penicillin nucleus, its initial prescription drug. From then on Beecham s evolution demonstrated parallels to those of the American producers in the advertising-intensive OTC path. 

The penicillin nucleus has been utilized for the construction of the dihy-drothiazine ring. Thus when treated with chromium(II) chloride, the... 

This situation changed when an efficient chemical method was developed at Eli Lilly in Indianapolis, which would remove the side-chain of cephalosporin C to produce a bare cephalosporin nucleus, the so-called 7-aminocephalosporanic acid, from which a whole range of semi-synthetic cephalosporins could be produced. Of these, cephaloridine and cephalothin were the most widely used. Of even greater significance was the invention of some very clever chemistry, also by the Lilly group, which involved the conversion of the penicillin nucleus into the cephalosporin nucleus in a short sequence of chemical transformations (Fig. 2.2). This meant that the very cheap penicillin G could be converted into what became the best-selling cephalopsorin cephalexin (Keflex). This had excellent oral bioavailability, was very stable to metabolism, and resisted the actions of penicillinases. The other semi-synthetic cephalosporin that came to be widely used was cefaclor... 

One should note particularly the structure of 6-aminopenicillanic acid (6APA), which has been termed the penicillin nucleus. Our announcement (13, 14) in March 1958 that .. . we have prepared this compound [6-aminopenicillanic acid (6APA)] via a totally synthetic route. .. We have shown that one can acylate with various acid chlorides and obtain the corresponding penicillins, together with the subsequent development of commercially attrac-... 

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