Penicillins modified

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). 

AH cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). AH of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfiiHy directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone ia the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequendy developed (22,23). The ready avaHabHity of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin stmcture offers more opportunities for chemical modification than does that of penicillins There are two side chains that especiaHy lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

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...

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

Semisynthesis. This means that part of the moleeule is produced by a fermentation proeess using the appropriate microorganism and the produet is then further modified by a ehemical process. Many penicillins and cephalosporins (seetion 2) are produced in this w. ... 

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... 

Lactam antibiotics, such as cephalosporins, and penicillins, such as ampicillin (11) and aztreonam, covalently modify their protein targets. Alkyne-functionalized versions of these antibiotics, for example, AmpN (12), were used to probe various penicillin-binding proteins in vitro and in vivo using CC-ABPP [36,37],... 

Besides, potentiometric sensors with ion-selective ionophores in modified poly(vinyl chloride) (PVC) have been used to detect analytes from human serum [128], Cellular respiration and acidification due to the activity of the cells has been measured with CMOS ISFETS [129], Some potentiometric methods employ gas-sensing electrodes for NH3 (for deaminase reactions) and C02 (for decarboxylase reactions). Ion-selective electrodes have also been used to quantitate penicillin, since the penicillinase reaction may be mediated with I or GST. 

In contrast to a-methyldopa-induced hemolytic anemia, most drug-induced hemolytic anemia, especially for penicillins [34] and cephalosporins [35], involves drug-dependent antibodies, presumably because the drug acts as a hapten to directly modify erythrocytes or form immune complexes [36], However, there are many examples where a drug, such as nomifensine, induces both drug- (or metabolite)-dependent and drug-... 

Autoantibodies to red blood cells and autoimmune hemolytic anemia have been observed in patients treated with numerous drugs, including procainamide, chlor-propaminde, captopril, cefalexin, penicillin, and methyldopa (Logue et al., 1970 Kleinman et al., 1984). Hydralazine- and procainamide-induced autoantibodies may also result in SLE. Approximately 20% of patients administered methyldopa for several weeks for the treatment of essential hypertension developed a dose-related titer and incidence of autoantibodies to erythrocytes, 1% of which presented with hemolytic anemia. Methlydopa does not appear to act as a hapten but appears to act by modifying erythrocyte surface antigens. IgG autoantibodies then develop against the modified erythrocytes. 

Resistance to antibiotics is usnally due to the acquisition of genes that express enzymes that can inactivate the antibiotics (e.g. P-lactamase degrades the lactam ring in penicillin (see below) or that can modify the structure of proteins that are necessary for the antibiotic to enter the... 

Penicillin and cephalosporin antibiotics are usually classed as P-lactam antibiotics, since their common feature is a lactam function in a four-membered ring, typically fused to another ring system. This second ring takes in the P-lactam nitrogen atom and also contains sulfur. In the case of penicillins, e.g. benzylpenicillin, the second ring is a thiazolidine, and in the cephalosporins, e.g. cephalosporin C, this ring is a dihydrothiazine. What is not readily apparent from these structures is that they are both modified tripeptides and their biosyntheses share a common tripeptide precursor. 

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