Of penicillins

Crowfoot D, Bunn C W, Rogers-Low B W and Turner-Jones A 1949 The X-ray orystallographio investigation of the struoture of penioiiiin Chemistry of Penicillin ed H T Ciarke, J R Johnson and R Robinson (Prinoeton, NJ Prinoeton University Press) pp 310-66... 

APA may be either obtained directly from special Penicillium strains or by hydrolysis of penicillin Q with the aid of amidase enzymes. A major problem in the synthesis of different amides from 6-APA is the acid- and base-sensitivity of its -lactam ring which is usually very unstable outside of the pH range from 3 to 6. One synthesis of ampidllin applies the condensation of 6-APA with a mixed anhydride of N-protected phenylglydne. Catalytic hydrogenation removes the N-protecting group. Yields are low (2 30%) (without scheme). 

The discoverer of penicillin Sir Alexander Fleming has appeared on two stamps This 1981 Hungarian issue includes both a likeness of Fleming and a structural for mula for penicillin... 

Mifflin, T. E. Andriano, K. M. Robbins, W. B. Determination of Penicillin Using an Immobilized Enzyme Electrode, /. Chem. Educ. 1984, 61, 638-639. 

Mifflin and associates described a membrane electrode for the quantitative analysis of penicillin in which the enzyme penicillinase is immobilized in a polyacrylamide gel that is coated on a glass pH electrode. The following data were collected for a series of penicillin standards. 

Construct a calibration curve for the electrode, and report (a) the range of concentrations in which a linear response is observed, (b) the equation for the calibration curve in this range, and (c) the concentration of penicillin in a sample that yields a potential of 142 mV. 

An optimum response was defined as the greatest sensitivity, as determined by the measured potential for a standard solution of penicillin, and the largest sampling rate. The results of the optimization studies are shown in the following... 

The behavior of drops in the centrifugal field has been studied (211) and the residence times and mass-transfer rates have been measured (212). PodbieHiiak extractors have been widely used in the pharmaceutical industry, eg, for the extraction of penicillin, and are increasingly used in other fields as weU. Commercial units having throughputs of up to 98 m /h (26,000 gal/h) have been reported. 

Antibiotics. Solvent extraction is an important step in the recovery of many antibiotics (qv) such as penicillin [1406-05-9] streptomycin [57-92-17, novobiocin [303-81-1J, bacitracin [1405-87-4] erythromycin, and the cephalosporins. A good example is in the manufacture of penicillin (242) by a batchwise fermentation. Amyl acetate [628-63-7] or -butyl acetate [123-86-4] is used as the extraction solvent for the filtered fermentation broth. The penicillin is first extracted into the solvent from the broth at pH 2.0 to 2.5 and the extract treated with a buffet solution (pH 6) to obtain a penicillin-rich solution. Then the pH is again lowered and the penicillin is re-extracted into the solvent to yield a pure concentrated solution. Because penicillin degrades rapidly at low pH, it is necessary to perform the initial extraction as rapidly as possible for this reason centrifugal extractors are generally used. 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporkis, a number of which are synthesized by acylation of fermentation-derived 7-amkiocephalosporanic acid, are an example. Two orally active cephalosporkis called cefroxadine and cephalexin are produced by a synthetic ring-expansion of penicillin V. 

Derivatiziag an organic compound for analysis may require only a few drops of reagent selected from silylatiag kits suppHed by laboratory supply houses. Commercial syathesis of penicillins requires silylatiag ageats purchased ia tank cars from the manufacturer (see Antibiotics, P-LACTAMS-penicillins AND others). 

Penicillins. Since the discovery of penicillin in 1928 as an antibacterial elaborated by a mold, Penicillium notatum the global search for better antibiotic-producing organism species, radiation-induced mutation, and culture-media modifications have been used to maximize production of the compound. These efforts have resulted in the discovery of a variety of natural penicillins differing in side chains from the basic molecule, 6-aminopenici11anic acid [551-16-6], These chemical variations have produced an assortment of dmgs having diverse pharmacokinetic and antibacterial characteristics (see Antibiotics, P-lactams). 

Historically, the development of penems is contemporary with that of the naturally occurring carbapenems and the direction of penem research has clearly been influenced by the stmctures of the closely related natural products. The origins of the two groups of compounds is, however, quite different. Unlike carbapenems, no penems have been found in nature. When first described (84,85) they were viewed as hybrid molecules combining stmctural features of penicillins and cephalosporins. 

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. 

Superior penicillin producing cultures ate capable of producing in excess of 30 mg/mL of penicillin G (154). Cephalosporin producing strains, however, generally grow poorly and cephalosporin C production is not as efficient as is that of penicillin. Factors such as strain maintenance, strain improvement, fermentation development, inoculum preparation, and fermentation equipment requkements ate discussed in the hterature (3,154). 

The P-lactam antibiotics ate produced by secondary metaboHc reactions that differ from those responsible for the growth and reproduction of the microorganism. In order to enhance antibiotic synthesis, nutrients must be diverted from the primary pathways to the antibiotic biosynthetic sequences. Although most media for the production of penicillins and cephalosporins are similar, they ate individually designed for the specific requkements of the high yielding strains and the fermentation equipment used. 

A typical fermentation medium for penicillin production contains lactose, com steep Hquot, and calcium carbonate (3,153,154). In most industrial processes the carbohydrate source, glucose, beet molasses, or lactose, is continuously added to the fermentation. The rate of glucose addition must be carefully monitored, by pH or rate of oxygen depletion, because the synthesis of penicillin is markedly reduced in the presence of excess glucose. 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

Landmarks in the development of penicillin are its discovery in 1929 (2) and the subsequent recognition in 1940 of the potential utiUty of penicillin for controlling antibacterial infections in animals (3) and shordy afterward in humans (4,5). The realization that penicillin was a usehil dmg occurred during WoddWar II (6). 

The analysis of penicillins by mass spectrometry (qv) has developed with the advent of novel techniques such as fast atom bombardment. The use of soft ionization techniques has enabled the analysis of thermally labile nonvolatile compounds. These techniques have proven extremely valuable in providing abundant molecular weight information from underivatized penicillins, both as free acids and as metal salts (15). 

The only penicillins used in their natural form are benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V). The remainder of penicillins in clinical use are derived from 6-APA and most penicillins having useful biological properties have resulted from acylation of 6-APA using standard procedures. 

Substitution of penicillins by 6a-methoxy was found to be compatible with an a-acidic side chain in terms of antibacterial activity, but less beneficial when the side chain contained an a-acyl or a-ureido substituent. However, analogues of the ureido penicillin VX-VC-43 (Table 2) containing a 6a-methoxy substituent (10) were found to combine good stabiUty to P-lactamase and relatively high antibacterial activity (37). Following an extensive program to identify other 6a-substituents that would stabilize the acyl and ureido series of penicillins, the 6a-formamido series (11) represented by formidacillin (BRL 36650) (Table 2) was developed (38). 

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