Penicillins and Derivatives

FIGURE 7.53 Structure of penicillin and derivatives arising by spontaneous transformation. For penicillin G, R=benzyl, R =protein. Adapted from De Week (1962) Int. Archs Allergy Appl. Immunol., 21, 20. 

Fertiiizers (N, P, K, Ca, Mg) Chior-alkali production (NaOH, NaCI, NaOCI, NaClOa) Pharmaceuticals Penicillin and derivatives... 

ANTTBIOTTCS - BETA-LACTAMS - PENICILLINS AND OTTiERS] (Vol 3) -pivaloyloxymethyl ester derivative [CARBOXYLIC ACIDS - TRIALKYLACETIC ACIDS] (Vol 5)... 

In the period up to 1970 most P-lactam research was concerned with the penicillin and cephalosporin group of antibiotics (1). Since that time, however, a wide variety of new mono- and bicychc P-lactam stmctures have been described. The carbapenems, characterized by the presence of the bicychc ting systems (1, X = CH2) originated from natural sources the penem ring (1, X = S) and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are 7-oxo-(R)-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxyhc acid [78854-41-8] CyH NO, and 7-oxo-(R)-4-thia-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxylic a.cid [69126-94-9], C H NO S, respectively. 

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously deterrnined from the ene-lactam (16). The resultant (R)-aspartic acid (17) demonstrated that the absolute stereochemistry at C-5 of thienamycin is (R), corresponding to that found in the C-5 position of both penicillins and cephalosporins. Confirmation of the stereochemical assignments in both thienamycin (2) and the olivanic acid MM 13902 (3, n = 0) has been confirmed by x-ray crystallography (19,21,22). The stmctural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

An intermolecular carbenoid reaction followed by intramolecular displacement of acetate gives the clavulanic acid derivative (112) in one step from 4-acetoxyazetidin-2-one (91) (80CC1257). Carbene-induced reactions of penicillins and cephalosporins have been reviewed (75S547, 78T1731). 

The acylation of 6-APA (Scheme 59) has been a very versatile way in which to generate new penicillin derivatives which differ from fermentation-produced penicillins in the 6-side chain. As will be discussed in Section 5.11.5.1, this approach has led to significant improvements in the therapeutic properties of penicillins, and, in fact, of the penicillins in medical use today, only benzylpenicillin and phenoxymethylpenicillin are produced directly by fermentation. 

Certain penicillins and penam derivatives have the ability to inhibit the /3-lactamase enzyme, and can provide a variable degree of protection to susceptible /3-lactam antibiotics... 

A number of di- and trisubstituted hydrazides of penicillin and cephalosporin derivatives were prepared to study the effect of A-substitution on ease of oxidative cleavage. ... 

Note It is reported that the use of chlorobenzene as solvent is essential when the reagent is to be used to detect aromatic amines [1]. In the case of steroids, penicillins, diuretics and alkaloids the reaction should be accelerated and intensified by spraying afterwards with dimethylsulfoxide (DMSO) or dimethylformamide (DMF), indeed this step makes it possible to detect some substances when this would not otherwise be possible [5,9-11] this latter treatment can, like heating, cause color changes [5,9]. Penicillins and diuretics only exhibit weak reactions if not treated afterwards with DMF [10, 11]. Steroids alone also yield colored derivatives with DMSO [9]. Tlreatment afterwards with diluted sulfuric acid (c = 2 mol/L) also leads to an improvement in detection sensitivity in the case of a range of alkaloids. In the case of pyrrolizidine alkaloids it is possible to use o-chloranil as an alternative detection reagent however, in this case it is recommended that the plate be treated afterwards with a solution of 2 g 4-(dimethyl-amino)-benzaldehyde and 2 ml boron trifluoride etherate in 100 ml anhydrous ethanol because otherwise the colors initially produced with o-chloranil rapidly fade [12]. 

Some substances, e. g. penicillin and pyrazolinone derivatives, are poorly detected by iodine staining with detection limits of 2-4 pg substance per chromatogram zone [6, 7]. The limits for lipids and for opium alkaloids lie with 50-500 ng [8] in the middle nanogram range [9]. 

The p-lactams (penicillins and their derivatives) are the drugs which most frequently cause IgE-mediated anaphylactic reactions. Diagnosis is based on skin tests. To date, the best vaUdated in vitro diagnostic methods are specific IgE and BAT. As for the determination of specific IgE using ImmimoCap (Phadia AB, Uppsala, Sweden), the sensitivity of the technique in the diagnosis of immediate reaction to (3-lactams with positive skin test ranges, according to the study, from 37 to 54% with a specificity of between 83 and 100% [23,24]. 

Lactams are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, carbapenems, and clavams (/8-lactamase inhibitors). The metabolic engineering of penicillin and cephalosporins production has been summarized by several good reviews [71,72], so the focus here is clavulanic acid, which has attracted interest in recent years. 

N-Benzyl-2,3-azetidinedione may be regarded as the most readily available of the unadorned a-keto-p-lactams. More complex analogs are of course known,5 particularly derivatives of the penicillin and cephalosporin antibiotics.7 All members feature a high density of functionality in a small ring and consequently hold considerable synthetic potential. The transformations shown below have already been recorded. 

Note that penicillins and structurally related antibiotics are frequently deactivated by the action of bacterial -lactamase enzymes. These enzymes also contain a serine residue in the active site, and this is the nucleophile that attacks and cleaves the P-lactam ring (see Box 7.20). The P-lactam (amide) linkage is hydrolysed, and then the inactivated penicillin derivative is released from the enzyme by further hydrolysis of the ester linkage, restoring the functional enzyme. The mode of action of these enzymes thus closely resembles that of the serine proteases there is further discussion in Box 7.20. 

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